5-Substituted-2-arylpyrazines

ABSTRACT

Novel 5-substituted-2-arylpyrazine compounds are provided. Such compounds can act as selective modulators of CRF receptors. The 5-substituted-2-arylpyrazine compounds provided herein are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided.  
     Compounds provided are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

[0001] The present application claims the benefit of U.S. provisionalapplication No. 60/405,013, filed Aug. 20, 2002, which is incorporatedherein by reference in its entirety.

BACKGROUND

[0002] 1. Field of the Invention

[0003] The present invention relates to 5-substituted-2-arylpyrazinecompounds. Such compounds bind with high selectivity and/or highaffinity to CRF1 receptors (Corticotropin Releasing Factor 1 Receptors).Preferred compounds block, inhibit, activate, or otherwise modulate theactivity of the receptors to which they bind. This invention alsorelates to pharmaceutical compositions comprising such compounds and tothe use of such compounds in treatment of psychiatric disorders andneurological diseases, including major depression, anxiety-relateddisorders, post-traumatic stress disorder, supranuclear palsy andfeeding disorders, as well as treatment of immunological, cardiovascularor heart-related diseases, irritable bowel syndrome, and colonichypersensitivity associated with psychopathological disturbance andstress. Additionally this invention relates to the use such compounds asprobes for the localization of CRFI receptors in cells and tissues.

[0004] 2. Background of the Invention

[0005] Corticotropin releasing factor (CRF), a 41 amino acid peptide, isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland. In additionto its endocrine role at the pituitary gland, immunohistochemicallocalization of CRF has demonstrated that the hormone has a broadextrahypothalamic distribution in the central nervous system andproduces a wide spectrum of autonomic, electrophysiological andbehavioral effects consistent with a neurotransmitter or neuromodulatorrole in brain. There is also evidence that CRF plays a significant rolein integrating the response of the immune system to physiological,psychological, and immunological stressors.

[0006] CRF acts by binding to and modulating the signal transductionactivities of specific cell surface receptors, including CRF1 receptorsand CRF2 receptors. These receptors are found at high concentrations inthe central nervous system (CNS), particularly in certain regions of thebrain. CRF1 receptors are also found outside the CNS.

[0007] Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system.

[0008] In affective disorder, or major depression, the concentration ofCRF is significantly increased in the cerebral spinal fluid (CSF) ofdrug-free individuals. Furthermore, the density of CRF receptors issignificantly decreased in the frontal cortex of suicide victims,consistent with a hypersecretion of CRF. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofCRF receptors in brain.

[0009] The mechanisms and sites of action through which conventionalanxiolytics and antidepressants produce their therapeutic effects remainto be fully elucidated. It has been hypothesized however, that they areinvolved in the suppression of CRF hypersecretion that is observed inthese disorders.

[0010] CRF has been implicated in the etiology of anxiety-relateddisorders. CRF produces anxiogenic effects in animals and interactionsbetween benzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxiety models. Preliminarystudies using the putative CRF receptor antagonist α-helical ovine CRF(9-41) in a variety of behavioral paradigms demonstrate that theantagonist produces “anxiolytic-like” effects that are qualitativelysimilar to the benzodiazepines. Neurochemical, endocrine and receptorbinding studies have all demonstrated interactions between CRF andbenzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test and in theacoustic startle test in rats. The benzodiazepine receptor antagonist Ro15-1788, which was without behavioral activity alone in the operantconflict test, reversed the effects of CRF in a dose-dependent manner,while the benzodiazepine inverse agonist FG 7142 enhanced the actions ofCRF.

[0011] CRF activity has also been implicated in the pathogeneisis ofcertain cardiovascular or heart-related, digestive, degenerative,dermatological, and immunological, diseases and disorders such ashypertension, tachycardia and congestive heart failure, stroke, acne andosteoporosis, as well as in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity, e.g., associated with psychopathological disturbanceand stress.

SUMMARY OF THE INVENTION

[0012] The invention provides novel compounds of Formula I (shownbelow). The invention also comprises pharmaceutical compositionscomprising compounds of Formula I and at least one pharmaceuticallyacceptable carrier or excipient. Such 5-substituted-2-arylpyrazines bindto cell surface receptors, preferably G-coupled protein receptors,especially CRF receptors and most preferably CRF1 receptors. Preferredcompounds of Formula I exhibit high affinity for CRF1 receptors, i.e.,they bind to, activate, inhibit, or otherwise modulate the activity ofreceptors other than CRF receptors with affinity constants of less than1 micromolar, preferably less than 100 nanomolar, and most preferablyless than 10 nanomolar. Additionally, preferred compounds of Formula Ialso exhibit high selectivity for CRF1 receptors.

[0013] The invention further comprises methods of treating patientssuffering from certain diseases or disorders by administering to suchpatients an amount of a compound of Formula I effective to reduce signsor symptoms of the disease or disorder. These diseases and disordersinclude CNS disorders, particularly affective disorders, anxiety,stress, depression, and eating disorders and also include certaindigestive disorders, particularly irritable bowel syndrome and Crohn'sdisease. These diseases or disorders further include cardiovascular orheart-related, digestive, degenerative, dermatological, andimmunological, diseases and disorders such as hypertension, tachycardiaand congestive heart failure, stroke, acne and osteoporosis, as well aspremature birth, psychosocial dwarfism, stress-induced fever, ulcer,diarrhea, post-operative ileus and colonic hypersensitivity. The patientsuffering from such diseases or disorders may be a human or other animal(preferably a mammal), such as a domesticated companion animal (pet) ora livestock animal.

[0014] According to yet another aspect, the present invention providespharmaceutical compositions comprising a compound of Formula I orpharmaceutically acceptable salts or solvates thereof together with atleast one pharmaceutically acceptable carrier or excipient, whichcompositions are useful for the treatment of the disorders recitedabove. The invention further provides methods of treating patientssuffering from any of these disorders with an effective amount of acompound or composition of Formula I.

[0015] Additionally this invention relates to the use of labeledcompounds of Formula I (particularly radiolabeled compounds of thisinvention) as probes for the localization of receptors in cells andtissues and as standards and reagents for use in determining thereceptor-binding characteristics of test compounds.

[0016] Thus, in a first aspect, the invention is directed to compoundsof Formula I

[0017] and the pharmaceutically acceptable salts thereof.

[0018] Ar is substituted phenyl, optionally substituted naphthyl, or anoptionally substituted heteroaryl group having from 1 to 3 rings, and 3to 8 ring members in each ring and from 1 to about 3 heteroatoms in atleast one of said rings.

[0019] R₂ is optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedalkylamino, optionally substituted alkoxy, optionally substitutedalkylthio, optionally substituted alkylsulfinyl, or optionallysubstituted alkylsulfonyl.

[0020] R₁ and R₃ are each independently hydrogen, halogen, cyano, nitro,amino, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted mono ordialkylamino, optionally substituted alkoxy, optionally substitutedalkylthio, optionally substituted alkylsulfinyl, or optionallysubstituted alkylsulfonyl.

[0021] If Ar is phenyl substituted with halogen, naphthyl, or naphthylsubstituted with halogen, then R₃ is not hydrogen or amino.

DETAILED DESCRIPTION OF THE INVENTION

[0022] Chemical Description and Terminology

[0023] Prior to setting forth the invention in detail, it may be helpfulto provide definitions of certain terms to be used herein. Compounds ofthe present invention are generally described using standardnomenclature. Certain compounds are described herein using a generalformula that includes variables. Unless otherwise specified, eachvariable within such a formula is defined independently of othervariables.

[0024] In certain situations, the compounds of Formula I may contain oneor more asymmetric elements such as stereogenic centers, stereogenicaxes and the like, e.g. asymmetric carbon atoms, so that the compoundscan exist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. For compounds with two ormore asymmetric elements, these compounds can additionally be mixturesof diastereomers. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. Where a compound exists in varioustautomeric forms, the invention is not limited to any one of thespecific tautomers, but rather includes all tautomeric forms. In thesesituations, the single enantiomers, i.e. optically active forms, can beobtained by asymmetric synthesis, synthesis from optically pureprecursors or by resolution of the racemates. Resolution of theracemates can be accomplished, for example, by conventional methods suchas crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column.

[0025] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example, and without limitation, isotopes of hydrogen includetritium and deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

[0026] When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

[0027] The term “substituted”, as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valenceis not exceeded, and that the substitution results in a stable compound.When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom arereplaced. When aromatic moieties are substituted by an oxo group, thearomatic ring is replaced by the corresponding partially unsaturatedring. For example a pyridyl group substituted by oxo is adihydropyridone.

[0028] As indicated above, various substituents of Formula I and FormulaIA and Formula I-Formula E (described below) are “optionallysubstituted”. The phrase “optionally substituted” indicates that suchgroups may either be unsubstituted or substituted at one or more of anyof the available positions, typically 1, 2, 3, or 4 positions, by one ormore suitable groups such as those disclosed herein.

[0029] When substituents such as Ar, R₁, R₂, R₃, and R₄, are furthersubstituted, they may be so substituted at one or more availablepositions, typically 1 to 3 or 4 positions, by one or more suitablegroups such as those disclosed herein. Suitable groups that may bepresent on a “substituted” Ar or other group include e.g., halogen;cyano; hydroxyl; nitro; azido; alkanoyl (such as a C₁₋₆ alkanoyl groupsuch as acyl or the like); carboxamido; alkyl groups (includingcycloalkyl groups, having 1 to about 8 carbon atoms, preferably 1, 2, 3,4, 5, or 6 carbon atoms); alkenyl and alkynyl groups (including groupshaving one or more unsaturated linkages and from 2 to about 8,preferably 2, 3, 4, 5 or 6, carbon atoms); alkoxy groups having one ormore oxygen linkages and from 1 to about 8, preferably 1, 2, 3, 4, 5 or6 carbon atoms; aryloxy such as phenoxy; alkylthio groups includingthose having one or more thioether linkages and from 1 to about 8 carbonatoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groupsincluding those having one or more sulfinyl linkages and from 1 to about8 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms;alkylsulfonyl groups including those having one or more sulfonyllinkages and from 1 to about 8 carbon atoms, preferably 1, 2, 3, 4, 5,or 6 carbon atoms; aminoalkyl groups including groups having one or moreN atoms and from 1 to about 8, preferably 1, 2, 3, 4, 5 or 6, carbonatoms; aryl having 6 or more carbons and one or more rings, (e.g.,phenyl, biphenyl, naphthyl, or the like, each ring either substituted orunsubstituted aromatic); arylalkyl having 1 to 3 separate or fused ringsand from 6 to about 18 ring carbon atoms, with benzyl being a preferredarylalkyl group; arylalkoxy having 1 to 3 separate or fused rings andfrom 6 to about 18 ring carbon atoms, with O-benzyl being a preferredarylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclicgroup having 1 to 3 separate or fused rings with 3 to about 8 membersper ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl,isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidyl, furanyl,pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl,imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such heterocyclic groups may be further substituted, e.g.with hydroxy, alkyl, alkoxy, halogen and amino.

[0030] Combinations of substituents and/or variables are permissibleonly if such combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture, and subsequent formulation into an effectivetherapeutic agent.

[0031] A dash (“-”) that is not between two letters or symbols is usedto indicate a point of attachment for a substituent. For example, —CONH₂is attached through the carbon atom.

[0032] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms. Thus, the term C₁₋₆ alkyl as usedherein includes alkyl groups consisting of 1 to 6 carbon atoms. WhenC₀-C_(n)alkyl is used herein in conjunction with another group, forexample, arylC₀-C₄alkyl, the indicated group, in this case aryl, iseither directly bound by a single covalent bond, or attached by an alkylchain having the specified number of carbon atoms, in this case from 1to 4 carbon atoms. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,and s-pentyl. Preferred alkyl groups are C₁₋₈ and C₁₋₆ alkyl groups.Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, and3-pentyl. “Carbhydryl” is intended to include both branched andstraight-chain hydrocarbon groups, which are saturated or unsaturated,having the specified number of carbon atoms.

[0033] “Alkenyl” is intended to include hydrocarbon chains of either astraight or branched configuration comprising one or more unsaturatedcarbon-carbon bonds, which may occur in any stable point along thechain, such as ethenyl and propenyl.

[0034] “Alkynyl” is intended to include hydrocarbon chains of either astraight or branched configuration comprising one or more triplecarbon-carbon bonds that may occur in any stable point along the chain,such as ethynyl and propynyl.

[0035] “Alkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through an oxygen bridge.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy,2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy,3-hexoxy, and 3-methylpentoxy.

[0036] “Alkoxycarbonyl” indicates a group of the formula:

[0037] The number of carbons listed, e.g. C₁₋₂alkoxycarbonyl, indicatesthe number of carbon atoms in the alkyl chain.

[0038] “Alkylcarboxamide” is a group of the formula —C(═O)NHalkyl.

[0039] As used herein, the term “mono- and di-alkylamino” includessecondary or tertiary alkyl amino groups, wherein the alkyl groups areas defined above and have the indicated number of carbon atoms. Thepoint of attachment of the alkylamino group is on the nitrogen. Examplesof mono- and di-alkylamino groups include ethylamino, dimethylamino,methylpropyl-amino. The term “mono- and di-alkylaminoalkyl” is used toindicate and alkyl group, as described above, substituted by a mono- ordi-alkylamino group, as described above.

[0040] As used herein, the term “aminoalkyl” indicates an alkyl groupsubstituted at the terminal position by NH₂, e.g. a 3-propylamine group.

[0041] As used herein, the term “alkylsulfinyl” includes those groupshaving one or more sulfoxide (SO) linkage groups and typically from 1 toabout 8 carbon atoms, more typically 1 to about 6 carbon atoms.

[0042] As used herein, the term “alkylsulfonyl” includes those groupshaving one or more sulfonyl (SO₂) linkage groups and typically from 1 toabout 8 carbon atoms, more typically 1 to about 6 carbon atoms.

[0043] As used herein, the term “alkylthio” includes those groups havingone or more thioether linkages and preferably from 1 to about 8 carbonatoms, more typically 1 to about 6 carbon atoms.

[0044] As used herein, the term “aryl” indicates aromatic groupscontaining only carbon in the aromatic ring. Such aromatic groups may befurther substituted with carbon or non-carbon atoms or groups. Typicalaryl groups contain 1 to 3 separate, fused, or pendant rings and from 6to about 18 ring atoms, without heteroatoms as ring members.Specifically preferred aryl groups include phenyl, naphthyl, including1-naphthyl and 2-naphthyl, and biphenyl. The definition of the term“aryl” is not identical to that of the variable “Ar”.

[0045] As used herein, “carbocyclic group” is intended to mean anystable 3- to 7-membered monocyclic group, which may be saturated,partially unsaturated, or aromatic. In addition to those exemplifiedelsewhere herein, examples of such carbocycles include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclohexenyl, and phenyl.

[0046] “Cycloalkyl” is intended to include saturated hydrocarbon ringgroups, having the specified number of carbon atoms, usually from 3 toabout 8 ring carbon atoms. Preferred cycloalkyl groups have from 3 to 7ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl and bridged or caged saturatedring groups such as norbornane or adamantane and the like.

[0047] In the term “(cycloalkyl)alkyl”, cycloalkyl and alkyl are asdefined above, and the point of attachment is on the alkyl group. Thisterm encompasses, but is not limited to, cyclopropylmethyl,cyclohexylmethyl, and cyclohexylmethyl. Likewise, in the term“(cycloalkyl)alkoxy”, cycloalkyl and alkoxy are as define above, and thepoint of attachment in the oxygen of the alkoxy group. The term“cycloalkyloxy” indicates a cycloalkyl group, as defined above, attachedthrough an oxygen bridge.

[0048] “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogenatoms. Examples of haloalkyl include, but are not limited to,trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0049] “Haloalkoxy” indicates a haloalkyl group as defined aboveattached through an oxygen bridge.

[0050] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, or iodo.

[0051] As used herein, the terms “heteroaryl” is intended to indicate astable 5-to 7-membered monocyclic or bicyclic or 7-to 10-memberedbicyclic heterocyclic ring which contains at least 1 aromatic ring thatcontains from 1 to 4 heteroatoms selected from N, O, and S, withremaining ring atoms being carbon. When the total number of S and Oatoms in the heteroaryl group exceeds 1, it is understood that theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1, 2,or 3, more typically 1 or 2. It is particularly preferred that the totalnumber of S and O atoms in the aromatic heterocycle is not more than 1.Examples of heteroaryl groups include pyridyl, indolyl, pyrimidinyl,pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl,triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline.

[0052] The term “heterocycloalkyl” is used to indicate saturated cyclicgroups containing from 1 to about 3 heteroatoms selected from N, O, andS, with remaining ring atoms being carbon. Heterocycloalkyl groups havefrom 3 to about 8 ring atoms, and more typically have from 5 to 7 ringatoms. Examples of heterocycloalkyl groups include morpholinyl,piperazinyl, and pyrrolidinyl groups.

[0053] As used herein, the term “heterocyclic group” is intended toinclude 3 to 7 membered saturated, partially unsaturated, or aromaticmonocyclic groups having at least one atom selected from N, O or S. Theremaining ring atoms are carbon. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Anitrogen atom in the heterocycle may optionally be quaternized. It ispreferred that the total number of heteroatoms in the heterocyclicgroups is not more than 4 and that the total number of S and O atoms inthe heterocyclic group is not more than 2, more preferably not more than1.

[0054] Preferred heterocyclic groups include, but are not limited to,pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and imidazolyl.

[0055] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making non-toxic acid or base salts thereof, and furtherrefers to pharmaceutically acceptable solvates of such compounds andsuch salts. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, dibesylic, sulfanilic, 2-acetoxybenzoic,fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,isethionic, HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Thepharmaceutically acceptable salts of the present invention can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

[0056] “Prodrugs” are intended to include any compounds that becomecompounds of Formula I when administered to a mammalian subject, e.g.,upon metabolic processing of the prodrug. Examples of prodrugs include,but are not limited to, acetate, formate and benzoate and likederivatives of functional groups (such as alcohol or amine groups) inthe compounds of Formula I.

[0057] The term “therapeutically effective amount” of a compound of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as anamelioration of symptoms, e.g., an amount effective to antagonize theeffects of pathogenic levels of CRF or to treat the symptoms of stressdisorders, affective disorder, anxiety or depression.

[0058] CRF1 Receptor Ligands

[0059] The present invention is based, in part, on the discovery thatsmall molecules having the general Formula I, shown above (as well aspharmaceutically acceptable salts and prodrugs thereof) act asantagonists and/or inverse agonists of CRF1 receptors.

[0060] In addition to compounds and pharmaceutically acceptable salts ofFormula I set forth above, the invention provides certain compounds ofFormula I, which will be referred to as compounds of Formula IA, inwhich R₁, R₂, R₃, and Ar carry the values set forth below.

[0061] Ar, in compounds of Formula IA, is phenyl, mono-, di-, ortri-substituted with RA, or Ar is selected from the group consisting of:naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, each of whichis unsubstituted or mono-, di-, or tri-substituted with RA.

[0062] R₁ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halogen, CN, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, mono- anddi-C₁₋₄alkylamino, C₁₋₄alkoxy, and S(O)_(n)(C₁₋₄ alkyl).

[0063] R₂ is selected from the group consisting of —XR_(C) and Y,wherein —X, R_(C), and Y are defined below.

[0064] R₃ is selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, mono- and di-C₁₋₄alkylamino, and —S(O)_(n)(C₁₋₄alkyl), C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and XR_(C).

[0065] R_(A) is independently selected at each occurrence from the groupconsisting of halogen, cyano, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, hydroxy,amino, and C₁₋₆alkyl optionally substituted with 0-2 R_(B), C₂₋₆ alkenylsubstituted with 0-2 R_(B), C₁₋₄ alkynyl substituted with 0-2 R_(B),C₃₋₇ cycloalkyl substituted with 0-2 R_(B), (C₃₋₇ cycloalkyl)C₁₋₄ alkylsubstituted with 0-2 R_(B), C₁₋₄ alkoxy substituted with 0-2 R_(B),—NH(C₁₋₄ alkyl) substituted with 0-2 R_(B), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl)each independently substituted with 0-2 R_(B), —XR_(C), and Y.

[0066] R_(B) is independently selected at each occurrence the groupconsisting of halogen, hydroxy, cyano, C₁₋₄alkyl, C₁-C₄alkoxy, mono- anddi-(C₁-C₄alkyl)amino, —S(O)_(n)(alkyl), halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, morpholino, pyrrolidino, piperidino, thiomorpholino,piperazino, 4-hydroxypiperidino, —S(O)_(n)(C₁₋₄alkyl), —CO(C₁₋₄alkyl),—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)(C₁₋₄alkyl), —XR_(C), and Y.

[0067] R_(C) and R_(D), are the same or different, and are independentlyselected at each occurrence from hydrogen, and straight, branched, andcyclic alkyl groups and (cycloalkyl)alkyl groups, having 1 to 8 carbonatoms, and containing zero or one or more double or triple bonds, eachof which 1 to 8 carbon atoms may be further substituted with one or moresubstituent (s) selected from oxo, hydroxy, halogen, C₁₋₄ alkoxy, mono-and di-C₁₋₄alkylamino, —NHC(═O)(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)C(═O)(C₁₋₄alkyl), —NHS(O)_(n)(C₁₋₄ alkyl), S(O)_(n)(C₁₋₄ alkyl), —S(O)_(n)NH(C₁₋₄alkyl), —S(O)_(n)N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and Z.

[0068] X is independently selected at each occurrence from the groupconsisting of —CH₂—, CHR_(D)—, —O—, —C(═O)—, —C(═O)O—, —S(O)_(n)—, —NH—,—NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—, S(O)_(n)NH—, —S(O)_(n)NR_(D)—,—OC(═S)S—, —NHC(═O)—, —NRDC(═O)—, —NHS(O)_(n)—, and —NRDS(O)_(n).

[0069] Y and Z are independently selected at each occurrence from 3- to7-membered carbocyclic and heterocyclic groups, which are saturated,partially unsaturated, or aromatic, which may be substituted with one ormore substituents selected from halogen, hydroxy, haloalkyl, oxo,hydroxy, amino, C₁₋₄ alkyl, C₁₋₄alkoxy, mono- and di-(C₁₋₄alkyl)amino,and S(O)_(n)(alkyl), wherein said 3- to 7-membered heterocyclic groupscontain from 1 to 3 heteroatom(s) selected from N, O, and S, withremaining ring atoms being carbon.

[0070] The variable “n” is independently selected at each occurrencefrom 0, 1, and 2.

[0071] If Ar, in a compound of Formula IA, is phenyl substituted withhalogen, naphthyl, or naphthyl substituted with halogen, then R₃ is nothydrogen.

[0072] In certain preferred compounds of the invention include compoundsand salts of Formula I of Formula IA in which Ar is substituted phenyl,preferably mono-, di-, or tri-substituted with R_(A).

[0073] The invention also includes compounds and salts of Formula I andFormula IA in which Ar is phenyl, mono-, di-, or tri-substituted withR_(A), and R₁ and R₃ are independently selected from the groupconsisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

[0074] The invention includes compounds of Formula I and Formula IA inwhich Ar is phenyl, mono-, di-, or tri-substituted with R_(A); and R_(C)and R_(D), are the same or different, and are independently straight,branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, whichcontain 0 or one or more double or triple bonds. In certain preferredcompounds and salts of this type R₁ and R₃ are independently selectedfrom the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy,and methoxy.

[0075] In addition, the invention includes certain compounds andpharmaceutically acceptable salts of Formula A

[0076] R₁, R₃, and Ar in Formula A carry the definitions set forth forFormula IA.

[0077] R_(X) and R_(Y), in Formula A, are the same or different and areindependently selected from straight, branched, and cyclic alkyl groupsand (cycloalkyl)alkyl group, having 1 to 8 carbon atoms, and containingzero or one or more double or triple bonds, each of which 1 to 8 carbonatoms may be further substituted with one or more substituent(s)independently selected from hydroxy, halogen, C₁₋₄ alkoxy, mono- anddi-(C₁₋₄ alkyl)amino, and optionally substituted phenyl.

[0078] The invention further provides compounds of Formula A in which:

[0079] R_(X) and R_(Y) carry the definitions set forth above forcompounds of Formula A.

[0080] Ar is phenyl, mono-, di-, or tri-substituted with R_(A) (whichcarries the definition set forth above for Formula IA).

[0081] R₁ and R₃ in these compounds are independently selected from thegroup consisting of hydrogen, halogen, methyl, ethyl, ethoxy andmethoxy.

[0082] The invention also provides compounds of Formula A in which:

[0083] Ar is phenyl, which is mono-, di-, or tri-substituted with one ormore substituent(s) independently selected from: halogen, cyano,C₁₋₂haloalkyl (preferably trifluoromethyl), C₁₋₂haloalkoxy (preferablytrifluoromethoxy), hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono-and di-(C₁₋₄ alkyl)amino.

[0084] More preferably Ar is a phenyl group of the formula:

[0085] wherein L indicates a bond to the pyrazine ring in Formula A; andthe phenyl group is substituted with the substituents list above for Argroups of Formula A at one, two or three of positions 2, 4, and 6.

[0086] R₁ and R₃, in these compounds, are independently chosen fromhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, mono- and di-(C₁₋₄alkyl)amino,C₁-C₂haloalkyl (preferably trifluoromethyl), C₁₋₂haloalkoxy (preferablytrifluoromethoxy).

[0087] R_(X), for certain preferred compounds is hydrogen; and R_(Y) ischosen from the group consisting of: straight, branched, or cyclic alkylgroups and (cycloalkyl)alkyl groups having 1 to 8 carbon atoms, andcontaining one or more double or triple bonds.

[0088] The invention provides compounds and pharmaceutically acceptablesalts of Formula A in which R₁, R₃, and Ar carry the definitions setforth for compounds of Formula IA and R_(X) and R_(Y) are independentlyhydrogen or C₁₋₈ alkyl; or R_(X) and R_(Y) are joined to form a group ofthe Formula

[0089] wherein z is 0 or 1.

[0090] Further provided by the invention are compounds andpharmaceutically acceptable salts of Formula B

[0091] R₁, R₃, and Ar in Formula B carry the definitions set forth forFormula IA.

[0092] R_(X), in Formula B is chosen from the group consisting of:straight, branched, or cyclic alkyl groups and (cycloalkyl)alkyl groups,having from 1 to 8 carbon atoms, containing zero or one or more doubleor triple bonds, each of which may be further substituted with one ormore substituent(s) independently selected from (a) hydroxy, halogen,—C₁₋₄ alkoxy, and mono- and di-(C₁₋₄alkyl)amino, and (b) 3- to7-membered carbocyclic and heterocyclic groups, which are saturated,partially unsaturated, or aromatic, which may be substituted with one ormore substituents selected from halogen, haloalkyl, oxo, hydroxy, amino,C₁₋₄ alkyl, C₁₋₄ alkoxy, and mono- and di-(C₁₋₄alkyl)amino and whereinsaid 3- to 7-membered heterocyclic groups contain one or moreheteroatom(s) selected from N, O, and S.

[0093] Preferred compounds of Formula B provided by the inventioninclude those compounds in which:

[0094] R_(X) is selected from straight, branched, and cyclic alkylgroups and (cycloalkyl)alkyl groups containing of 1 to 8 carbon atoms,having zero or one or more double or triple bonds.

[0095] R₁ and R₃, in these compounds of Formula C, are independentlychosen at each occurrence from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, mono-and di-(C₁₋₄ alkyl)amino, —C₁-C₂haloalkyl (preferably trifluoromethyl),and C₁₋₂haloalkoxy (preferably trifluoromethoxy).

[0096] Ar is phenyl, which is mono-, di-, or tri-substituted with one ormore substituent(s) independently selected from: halogen, cyano,C₁-C₂haloalkyl (preferably trifluoromethyl), C₁₋₂haloalkoxy (preferablytrifluoromethoxy), hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₄)amino(C₁₋₄alkoxy), and mono- anddi-(C₁₋₄ alkyl)amino.

[0097] More preferably Ar is a phenyl group of the formula:

[0098] wherein L indicates a bond to the pyrazine ring in Formula B; andthe phenyl group is substituted at one, two or three of positions 2, 4,and 6 with substituents independently chosen from those listed above forAr group of compounds of Formula B. Other preferred compounds of FormulaB include those wherein Ar is a phenyl group of the formula shownimmediately above, substituted positions 2 and 4 with substituentsindependently chosen from those listed above for Ar group of compoundsof Formula B.

[0099] The invention also provides compounds and pharmaceuticallyacceptable salts of Formula C and Formula D

[0100] R₁ and R₃, in Formula C and Formula D, are independently chosenat each occurrence from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, mono- anddi-(C₁₋₄ alkyl)amino, —C₁-C₂haloalkyl (preferably trifluoromethyl), andC₁₋₂haloalkoxy (preferably trifluoromethoxy). Preferably R₁ and R₃ areindependently selected from the group consisting of hydrogen, halogen,methyl, ethyl, ethoxy and methoxy.

[0101] Ar, in Formula C and Formula D, is a phenyl group of the formula:

[0102] wherein L indicates a bond to the pyrazine ring in Formula C andFormula D; and the phenyl group is substituted at one, two or three ofpositions 2, 4, and 6 with substituent(s) independently selected from:halogen, cyano, —C₁-C₂haloalkyl (preferably trifluoromethyl), andC₁₋₂haloalkoxy (preferably trifluoromethoxy),hydroxy, amino, and C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- ordi(C₁₋₄alkyl)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino. Otherpreferred compounds of Formula C and Formula D include those wherein Aris a phenyl group of the formula shown immediately above, substitutedpositions 2 and 4 with substituents independently chosen from thoselisted above for Ar group of Formula C or Formula D.

[0103] The invention further provides compounds and pharmaceuticallyacceptable salts of Formula E

[0104] G, in Formula E, is oxygen or NH.

[0105] R_(X) is straight or branched chain C₁₋₈alkyl.

[0106] R₁ and R₃ are independently selected from hydrogen, C₁₋₄ alkyl,halogen, C₁₋₂ haloalkyl,

[0107] C₁₋₂haloalkoxy, mono- and di-C₁₋₄alkylamino, C₁₋₄alkoxy, and C₁₋₄alkylthio.

[0108] R₅ is halogen, C₁₋₆alkyl, preferably C₁₋₄alkyl, or C₁₋₆alkoxy,preferably C₁₋₄alkoxy, each of which may be optionally substituted withone or more groups such as hydroxy, C₁₋₄alkoxy or the like.

[0109] R₆ is hydrogen, halogen, C₁₋₆alkyl, preferably C₁₋₂alkyl, orC₁₋₆alkoxy, preferably C₁₋₂alkoxy, each of which may be optionallysubstituted with one or more groups such as hydroxy, C₁₋₄alkoxy or thelike.

[0110] R₇ is halogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₂haloalkyl, C₁₋₂haloalkoxy, mono- and di-C₁₋₄alkylamino, mono- anddi-(C₁₋₂alkyl)aminoC₁₋₄alkyl, C₁₋₂alkoxyC₁₋₄alkyl, C₁₋₂alkoxycarbonyl,C₁₋₂alkylcarboxaminde, —C(═O)NH₂, hydroxyC₁₋₂alkyl,trifluoromethylsulfonyl, 2,2,2-trifluoroethanol, or a 4-7 memberedheterocycloalkyl group containing 1 or 2 atoms independently chosen fromN, O, and S, each of which may be optionally substituted with one ormore groups such as hydroxy, C₁₋₄alkoxy or the like.

[0111] R₈ is hydrogen, halogen, C₁₋₄alkyl, preferably C₁₋₂alkyl,C₁₋₂alkoxy, preferably C₁₋₂alkoxy, or mono or diC₁alkylamino which maybe optionally substituted with one or more groups selected from halogen,hydroxy, C₁₋₄alkoxy, or a 4-7 membered heterocycloalkyl group containing1 or 2 atoms independently chosen from N, O, and S

[0112] J is N or CR₉ where R₉ is hydrogen, halogen or C₁₋₂alkyl.

[0113] Certain preferred compounds and salts according to Formula Einclude those compounds in which R₁ and R₃ are not hydrogen. Theinvention comprises compounds and salts of Formula E in which J isnitrogen and R₆ is hydrogen. The invention also comprises compounds andsalts of Formula E in which J is CH and R₆ is hydrogen.

[0114] The invention further provides compounds or salts of Formula Ewherein G is NH and R_(X) is 1-ethyl propyl. Particularly preferredcompounds and salts of Formula E include those compounds in which R₁ iscyano, methoxy, or methylthio and R₃ is methyl or ethyl when G is NH andR_(X) is 1-ethylpropyl.

[0115] The invention also provides compounds and salts of Formula Ewherein G is oxygen and R_(X) is 1-ethylpropyl,1-isopropyl-2-methypropyl, 1-propylbutyl, or 1-ethylbutyl. It ispreferred that R₃ is halogen, C₁₋₂alkyl, or methylamino for compoundsand salts of these compounds. It is also preferred that R₁ is halogen,methyl, methoxy, ethyl, ethoxy, or C₁₋₂alkylamino for compounds andsalts of these compounds of Formula E. Compounds and salts of Formula Ein which G is oxygen, Rx is a branched chain alkyl, e.g. -ethylpropyl, 1isopropyl-2-methypropyl, 1-propylbutyl, or 1-ethylbutyl, and R₁ ismethylamino are also preferred.

[0116] Certain preferred Ar groups for compounds of Formula I, IA, andA-D, include, but are not limited to2-methoxy-4-(trifluoromethoxy)phenyl, 4-tert-butyl-2-methoxyphenyl, 4isopropyl-2-methoxyphenyl, 2,6-dimethoxypyridin-3-yl (i.e. the numberingof the pyridine ring begins at 1 on the nitrogen and the pyridine isattached to the pyrazine core at the 3 position),4-ethyl-2-methoxyphenyl, 2-chloro-4-(difluoromethoxy)phenyl,2-fluoro-4,6-dimethoxy-phenyl, 4-(difluoromethoxy)-2-methoxyphenyl,2-methoxy-6-dimethylaminopyridin-3-yl,2,5-diethyl-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)pyrazine,and the like.

[0117] Preferred compounds of Formula I exhibit a K_(i) value of 1micromolar or less in a standard in vitro CRF receptor binding assay.More preferred compounds exhibit a K_(i) value of 100 nanomolar or lessin a standard in vitro CRF receptor binding assay. Particularlypreferred compounds of Formula I exhibit a K_(i) value of 10 nanomolaror less in a standard in vitro CRF receptor binding assay. A standard invitro CRF1 receptor binding assay is disclosed in Example 30, below.

[0118] The invention further provides intermediates useful in thepreparation of compounds of Formula I, Formula IA, any the particularsubformula thereof (e.g., Formula II-Formula E), or any of the compoundsof Formula I specifically disclosed herein. Intermediates useful in thesynthesis of compounds in the invention are described in Schemes I-IVbelow, and further illustrated in Examples 1-28. For example, usefulintermediates provided by the invention include aryl metallo compoundsand aryl boronic acids useful for coupling to the pyridine core ofFormula I. Particular examples of such intermediates include, forexample 4-methoxy-2-methylbenzeneboronic acid,2-Methoxy-6-isopropyl-3-pyridylboronic acid (step 3, example 4), and4-Trifluoromethoxy-2-methoxy-phenylboronic acid (see step 6, example 5).

[0119] The invention also provides pharmaceutical compositionscomprising a compound, pharmaceutically acceptable salt, or prodrug ofFormula I, Formula IA, any the particular subformula thereof (e.g.,Formula A-Formula E), or any of the compounds of Formula I specificallydisclosed herein, together with a pharmaceutically acceptable carrier orexcipient. Pharmaceutically acceptable carriers suitable for use in acomposition provided by the invention may be inert, or may modulate thebioavailability or stability of the active compound. Representativecarriers include, for example, molecules such as albumin, polylysine,polyamidoamines, peptides, proteins, polystyrene, polyacrylamide,lipids, ceramide and biotin, solid support materials such as beads andmicroparticles comprising, for example, polyacetate, polyglycolate,poly(lactide-co-glycolide), polyacrylate, starch, cellulose or dextran.The pharmaceutical composition, may be prepared in a variety of forms,for example, as an injectable fluid, an aerosol, a cream, a gel, a pill,a capsule, a syrup, or a transdermal patch.

[0120] The invention also provides packages comprising a pharmaceuticalcomposition as described immediately above in a container andinstructions for using the composition to treat a patient suffering fromanxiety, or instructions for using the composition to treat a patientsuffering from stress, or instructions for using the composition totreat a patient suffering from depression, or instructions for using thecomposition to treat a patient suffering from irritable bowel syndromeor instructions for using the composition to treat a patient sufferingfrom Crohn's disease.

[0121] The CRF binding compounds provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of other compounds (e.g., a potentialpharmaceutical agent) to bind to the CRF receptor.

[0122] The invention provides a method for demonstrating the presence ofCRF receptors (preferably CRF1 receptors) in a biological sample (e.g.,a tissue section or homogenate), said method comprising contacting thebiological sample with a labeled compound of Formula I under conditionsthat permit binding of the labeled compound to a CRF receptor anddetecting the labeled compound in the biological sample. Unbound labeledcompound is preferably at least partially removed from the biologicalsample prior to detecting the bound labeled compound in the sample.

[0123] For detection purposes the compound may be labeled, for example,with a fluorescent, isotopic, or radiolabel. Radiolabeled andisotopically labeled compounds of Formula I, IA, and A-D, which are alsoincluded in the invention, are identical to the compounds recited inFormulae I, IA, and A-D, with one or more atoms replaced by an atomhaving an atomic mass or mass number different from the most highlyabundant isotope of that atom. Examples of isotopes that can beincorporated into compounds of Formula I in accordance with this aspectof the invention includes isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl. PREPARATION OF suchradiolabeled compounds of Formula I is described below in Example 31.The labeled compound may be detected if radiolabeled, e.g.,autoradiographically, and if otherwise isotopically labeled, e.g., byNMR. Labeled derivatives of the CRF antagonist compounds of Formula Iare also useful as radiotracers for positron emission tomography (PET)imaging or for single photon emission computerized tomography (SPECT).

[0124] The present invention also pertains to methods of inhibiting thebinding of CRF to CRF receptors which methods involve contacting asolution containing a compound of Formula I with at least one cell(e.g., a neuronal cell) expressing CRF receptors (e.g., preferably CRF1receptors), wherein the compound is present in the solution at aconcentration sufficient to inhibit CRF binding to CRF receptors invitro. This method includes inhibiting the binding of CRF to CRFreceptors in vivo in an animal (e.g., preferably a human patient). Theanimal is given an amount of a compound of Formula I that results in aconcentration in a relevant body fluid (e.g., blood, plasma, serum, CSF,interstitial fluid) of the animal, which concentration is at leastsufficient to inhibit the binding of CRF to CRF receptors in vitro.

[0125] The present invention also pertains to methods of altering (i.e.increasing or decreasing) the CRF-stimulated activity of CRF receptors,which methods involve contacting a solution containing a compoundFormula I with at least one cell (e.g., a neuronal cell) expressing CRFreceptors (e.g., preferably CRF1 receptors), wherein the compound ispresent in the solution at a concentration sufficient to alter theCRF-stimulated signal transduction activity of CRF receptors in cellsexpressing CRF receptors (preferably cells expressing such receptors atlevels above those found in naturally occurring CRF receptor-expressingcells) in vitro. This method includes altering the CRF-stimulatedactivity of CRF receptors in vivo in an animal (e.g., preferably a humanpatient). The animal is given an amount of a compound of Formula I thatresults in compound a concentration in a relevant body fluid (e.g.,blood, plasma, serum, CSF, interstitial fluid) of the animal, whichconcentration is at least sufficient to alter the CRF-stimulatedactivity of CRF receptors in vitro.

[0126] Certain preferred methods of the invention are useful in treatingphysiological disorders associated with excess concentrations of CRF ina patient (e.g., in a body fluid of the patient). The amount of acompound that would be sufficient to inhibit the binding of a CRF to aCRF receptor or to alter the CRF-stimulated activity of CRF receptorsmay be readily determined via a CRF receptor binding assay (see Example30), or from the EC₅₀ of a CRF receptor functional assay. CRF receptorsthat may be used to determine in vitro binding are found in a variety ofsources, for example in cells that autologously express CRF receptors,e.g. IMR32 cells, or in a cell expressing a CRF receptor as a result ofthe expression of an exogenous CRF receptor-encoding polynucleotidecomprised by the cell.

[0127] Methods of Treatment

[0128] Compounds of Formula I are useful in treating a variety ofconditions including affective disorders, anxiety disorders, stressdisorders, eating disorders, digestive disorders, and drug addiction.

[0129] Affective disorders include all types of depression, bipolardisorder, cyclothymia, and dysthymia.

[0130] Anxiety disorders include generalized anxiety disorder, panic,phobias and obsessive-compulsive disorder.

[0131] Stress, includes, for example, post-traumatic stress disorder,hemorrhagic stress, stress-induced psychotic episodes, psychosocialdwarfism, stress headaches, stress-induced immune systems disorders suchas stress-induced fever, and stress-related sleep disorders.

[0132] Eating disorders include anorexia nervosa, bulimia nervosa, andobesity.

[0133] Digestive disorders include, but are not limited to, irritablebowel syndrome and Crohn's disease.

[0134] Modulators of the CRF receptors may also be useful in thetreatment of a variety of neurological disorders including supranuclearpalsy, AIDS related dementias, multiinfarct dementia, neurodegenerativedisorders such as Alzheimer's disease, Parkinson's disease, andHuntington's disease, head trauma, spinal cord trauma, ischemic neuronaldamage, amyotrophic lateral sclerosis, disorders of pain perception suchas fibromyalgia and epilepsy.

[0135] Additionally compounds of Formula I are useful as modulators ofthe CRF receptor in the treatment of a number of gastrointestinal,cardiovascular, hormonal, autoimmune and inflammatory conditions. Suchconditions include ulcers, spastic colon, diarrhea, post operative iliusand colonic hypersensitivity associated with psychopathologicaldisturbances or stress, hypertension, tachycardia, congestive heartfailure, infertility, euthyroid sick syndrome, inflammatory conditionseffected by rheumatoid arthritis and osteoarthritis, pain, asthma,psoriasis and allergies.

[0136] Compounds of Formula I are also useful as modulators of the CRF1receptor in the treatment of animal disorders associated with aberrantCRF levels. These conditions include porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, and dysfunctions inducedby confinement in chickens, sheering stress in sheep or human-animalinteraction related stress in dogs, psychosocial dwarfism andhypoglycemia.

[0137] Typical subjects to which compounds of Formula I may beadministered will be mammals, particularly primates, especially humans.For veterinary applications, a wide variety of subjects will besuitable, e.g. livestock such as cattle, sheep, goats, cows, swine andthe like; poultry such as chickens, ducks, geese, turkeys, and the like;and domesticated animals particularly pets such as dogs and cats. Fordiagnostic or research applications, a wide variety of mammals will besuitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates, and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids and cell samples of the abovesubjects will be suitable for use such as mammalian, particularlyprimate such as human, blood, urine or tissue samples, or blood urine ortissue samples of the animals mentioned for veterinary applications.

[0138] Pharmaceutical Preparations

[0139] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrathecal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired, other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0140] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0141] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0142] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl phydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0143] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example peanut oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0144] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0145] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or peanut oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

[0146] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, or flavoringor coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also besterile an injectable solution or suspension in a non-toxic parentallyacceptable dilutent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0147] The compounds of general Formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0148] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0149] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

[0150] Frequency of dosage may also vary depending on the compound usedand the particular disease treated. However, for treatment of most CNSdisorders, a dosage regimen of 4 times daily or less is preferred. Forthe treatment of stress and depression a dosage regimen of 1 or 2 timesdaily is particularly preferred.

[0151] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0152] Preferred compounds of Formula I will have certainpharmacological properties. Such properties include, but are not limitedto oral bioavailability, optimal volume of distribution, low toxicity,low serum protein binding, and desirable in vitro and in vivohalf-lifes. Penetration of the blood brain barrier for compounds used totreat CNS disorders is necessary, while low brain levels of compoundsused to treat periphereal disorders are often preferred.

[0153] Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

[0154] Serum protein binding may be predicted from albumin bindingassays. Such assays are described in a review by Oravcova, et al.(Journal of Chromatography B (1996) volume 677, pages 1-27).

[0155] Compound half-life is inversely proportional to the frequency ofdosage of a compound. In vitro half-lives of compounds may be predictedfrom assays of microsomal half-life as described by Kuhnz and Gieschen(Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

[0156] As discussed above, preferred arylpyrazines of Formula I exhibitactivity in standard in vitro CRF receptor binding assays, specificallythe assay as specified in Example 30, which follows. References hereinto “standard in vitro receptor binding assay” are intended to refer tothat protocol as defined in Example 30 which follows. Generallypreferred arylpyrazines of Formula I have a K_(i) of about 1 micromolaror less, still more preferably a K_(i) of about 100 nanomolar or lesseven more preferably a K_(i) of about 10 nanomolar or less or even 1nanomolar or less in such a defined standard in vitro CRF receptorbinding assay as exemplified by Example 30 which follows.

ExampleS

[0157] PREPARATION OF 5-SUBSTITUTED-2-ARYLPYRAZINES

[0158] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Each of the referencescited below are hereby incorporated herein by reference. Preferredmethods for the preparation of compounds of the present inventioninclude, but are not limited to, those described in Schemes I-IV. Thosewho are skilled in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention. All references cited herein arehereby incorporated in their entirety herein by reference. The followingabbreviations are used herein: AcOH acetic acid DMFN,N-dimethylformamide Et₂0 diethyl ether EtOAc ethyl acetate EtOHethanol NaH sodium hydride NaHMDS sodium bis(trimethylsilyl)amide THFtetrahydrofuran CPD# compound number

[0159]

[0160] According to the general method A, wherein R₁ and R³ are asdefined for Formula I and Hal represents a halogen atom, suitablychloride or bromide, the halide in VI can be displaced by an amine or(thio)alkoxide nucleophile. Thus, aminopyrazine can be prepared from VIand an amine in the presence of a suitable transition metal catalystsuch as but not limited to palladium(II) acetate ortris(dibenzylideneacetone)dipalladium(0), a ligand such as but notlimited to 1,1′-bis(diphenylphosphine)ferrocene,2,2′-bis(diphenylphosphine)-1,1′binaphthyl,dicyclohexyl(2-biphenyl)phosphine, tricyclohexylphosphine, ortri-tertbutylphosphine, and a base such as sodium or potassiumtert-butoxide in inert solvents such as but not limited to toluene,ethyleneglycol dimethyl ether, diglyme, DMF, or N-methylpyrrolidinone attemperatures ranging from ambient to 100° C. (Thio)alkoxypyrazines canbe prepared by treating VI with a sodium or potassium salt of an alcoholor thiol in an inert solvent such as THF, DMF, N-methylpyrrolidinone, ormethyl sulfoxide at ambient temperature or at elevated temperature up tothe boiling point of the solvent employed. Halogenation may beaccomplished by a variety of methods known in the art, includingtreatment with N-chlorosuccinimide, bromine, N-bromosuccinimide,pyridinium tribromide, triphenylphosphine dibromide, iodine, andN-iodosuccinimide in solvents such as but not limited todichloromethane, acetic acid, or methyl sulfoxide. The bromopyrazine canbe converted to arylpyrazine VII by a transition metal-catalyzedcoupling reaction with a metalloaryl reagent (Ar-[M]). More commonlyemployed reagent/catalyst pairs include aryl boronic acid/palladium(0)(Suzuki reaction; N. Miyaura and A. Suzuki, Chemical Review 1995, 95,2457), aryl trialkylstannane/palladium(0) (Stille reaction; T. N.Mitchell, Synthesis 1992, 803), arylzinc/palladium(0) and arylGrignard/nickel(II). Palladium(0) represents a catalytic system made ofa various combination of metal/ligand pair which includes, but notlimited to, tetrakis(triphenylphosphine)palladium(0), palladium(II)acetate/tri(otolyl)phosphine,tris(dibenzylideneacetone)dipalladium(0)/tri-tert-butylphosphine anddichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(0). Nickel(II)represents a nickel-containing catalyst such as[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) and[1,3-bis(diphenylphosphino)propane]dichloronickel(II). The arylpyrazineVII, when X is NH, may be further transformed to VIII by N-alkylation.The N—H group is deprotonated by a strong base such as but not limitedto alkali metal hydride, alkali metal amide, or alkali metal alkoxide ininert solvents such as but not limited to THF, DMF, or methyl sulfoxide.Alkylation may be conducted using alkyl halide, suitably bromide oriodide, at temperatures ranging from 0° C. to 100° C.

[0161] In an alternative way, compounds of Formula VII can be preparedas outlined in Scheme II. Transition metal-catalyzed coupling of thehalo pyrazine VI as described in the Method A can provide theintermediate VIII. Oxidation of sterically less hindered nitrogen can beeffected by using a variety of oxidizing agents known in the art, whichincludes m-chloroperoxybenzoic acid, trifluoroperacetic acid, hydrogenperoxide, and monoperoxyphthalic acid. The N-oxide can undergorearrangement to give chloropyrazine IX upon the action of phosphorusoxychloride at temperatures ranging from ambient to 100° C. Displacementof the chloride with a nitrogen, oxygen, or sulfur nucleophile asdescribed in the Method A can furnish the compounds of Formula VII.

[0162] Yet another way of preparing compounds of Formula VII isillustrated in the Scheme III. Compounds of Formula X,3,6-dialkyl-2,5-dichloropyrazines, can be prepared from 215 alkylglycineaccording to a known literature procedure (Ref: Chemical andPharmaceutical Bulletin of Japan 1979, 27, 2027). Nucleophilicdisplacement of one chloride followed by Suzuki-type coupling at theother, as described in the Method A, can furnish the compounds ofFormula VII.

[0163] Still another way of preparing compounds of Formula VII isillustrated in Scheme IV. Commercially available 2,6-Dichloropyrazinecan undergo monosubstitution with nitrogen, oxygen, or sulfurnucleophile to give XI. Thus, X may react with an amine in solvents suchas but not limited to dichloromethane, acetonitrile, THF, DMF,N-methylpyrrolidinone, methyl sulfoxide, methanol, ethanol, andisopropanol at temperatures ranging from 0° C. to the boiling point ofthe solvent. In addition, X may react with a sodium or potassium(thio)alkoxide in inert solvents such as but not limited to THF, DMF,N-methylpyrrolidinone, or methyl sulfoxide at temperatures ranging from0° C. to ambient temperature. Resulting monochloropyrazine XI can behalogenated by using the conditions described in the Method A to give amixture of regioisomeric bromides XIa and XIb. Transitionmetal-catalyzed (hetero)aryl-aryl coupling of XIa, as described in theMethod A, followed by another halogenation can provide VII (R₁=Hal,R₃=Cl) which can be further converted to VII by displacing one or bothof the halogen atoms, either sequentially or simultaneously, with avariety of nucleophiles (R₁-[M] and R₃-[M]), same or different, in thepresence or absence of a transition metal catalyst. The aforementionednucleophiles may include sodium or potassium (thio)alkoxide, alkylamine,and organometallic reagent such as but not limited to alkyl Grignardreagents, alkylboronic acids or its ester, or alkylstannanes. Theaforementioned transition metal catalyst may represent palladium ornickel catalysts described in the Method A. The other regioisomericbromide XIb can also be converted to VII by changing the order of thetransformation sequence. Those who are skilled in the art will alsorecognize that one can further change the order of transformations toprepare the compounds of Formula VII by way of the intermediate XIII.

[0164] The preparation of the compounds of the present invention isillustrated further by the following examples, which are not to beconstrued as limiting the invention in scope or spirit to the specificprocedures and compounds described in them.

[0165] Commercial reagents were used without further purification. Roomor ambient temperature refers to 20 to 25° C. Concentration in vacuoimplies the use of a rotary evaporator. TLC refers to thin layerchromatography. Proton nuclear magnetic resonance (¹H NMR) spectral datawere obtained at 300 or 400 MHz. Mass spectral data were obtained eitherby CI or APCI methods.

Example 1 PREPARATION OF[N-(1-ETHYL)PROPYL]-5-(2,4-DIMETHOXYPHENYL)-3,6-DIMETHYLPYRAZINE-2-AMINE[Formula I: Ar=2,4-dimethoxyphenyl; R₂=—N-(1-ethyl)propyl; R₁=R₃═CH₃]

[0166] A. 1-ethylpropylamine (1.0 mmol) followed by sodium tert-butoxide(1.25 mmol) is added to a mixture of 2-chloro-3,6-dimethylpyrazine (0.83mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mol %), and BINAP (6mol %) in ethyleneglycol dimethyl ether (2 mL) under nitrogen. Themixture is stirred at 70-80° C. for 2.5 hours, diluted with aqueousammonium chloride, and extracted 1:1 hexane-Et₂O. Combined extracts aredried (sodium sulfate), filtered, concentrated, and chromatographed onsilica gel (10:1 to 4:1 hexane-EtOAc eluent) to give the aminopyrazine.

[0167] B. A solution of N-(1-ethyl)propyl-3,6-dimethylpyrazine-2-amine(0.72 g; 3.7 mmol) in dichloromethane (20 mL) is cooled to 0° C. andN-bromosuccinimide (0.72 g; 4.1 mmol) is added in portions. After theaddition, the mixture is further stirred for 1 hour while being allowedto warm to room temperature. The mixture is then concentrated to a smallvolume in vacuo, triturated with hexane, filtered, washed with hexane,and the filtrate is concentrated and chromatographed on silica gel togive the bromide (1.07 g).

[0168] C. A mixed solution of5-bromo-[N-(1-ethyl)propyl]-3,6-dimethylpyrazine-2-amine (0.40 g; 1.47mmol) and tetrakis(triphenylphosphine)palladium(0) (33 mg; 2 mol %) inethyleneglycol dimethyl ether (8 mL) is stirred at room temperature for15 minutes, after which 2,4-dimethoxybenzeneboronic acid (1.76 mmol) andan aqueous solution of sodium carbonate (1.0M, 4 mL) are addedsequentially. The mixture is heated to 75 C with stirring for 1.5 hours,then diluted with 0.1N sodium hydroxide and extracted twice with 1:1hexane-ethyl ether. Combined extracts are dried (sodium sulfate),filtered, concentrated, and chromatographed on silica (4:1 to 1:1hexane-EtOAc) to give the title compound (0.50 g): 1H MR (CDCl₃, 400MHz) δ 0.95 (t, 6H), 1.6 (m, 4H), 2.2 (s, 3H), 2.4 (s, 3H), 3.75 (s,3H), 3.85 (s, 3H), 3.95 (br d, 1H), 4.1 (br q, 1H), 6.5 (s, 1H), 6.55(d, 1H) 7.2 (d, 1H); MS (CI)

[0169] 330.

Example 2 PREPARATION OF[N-(1-ETHYL)PROPYL]-3,6-DIMETHYL-5-(2,4,6-TRIMETHYLPHENYL)PYRAZINE-2-Amine. [Formula I: Ar=2,4,6-trimethylphenyl;R₂=—N-(1-ETHYL(PROPYL; R₁=R₃=CH₃]

[0170] [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (40 mg) isadded to a solution of5-bromo-[N-(1-ETHYL(PROPYL]-3,6-dimethylpyrazine-2-amine (200 mg)obtained as in Example 1B in THF (4 mL) at room temperature is added.After 10 minutes, 2,4,6-trimethylphenylmagnesium bromide (1.0M in THF, 4mL) is added dropwise and slowly. The mixture is stirred at roomtemperature for 1 day, and then refluxed overnight. The resulting darksolution is poured into aqueous ammonium chloride and extracted twicewith ether. Combined extracts are dried (sodium sulfate), filtered,concentrated, and chromatographed to give the desired product (87 mg):¹H NMR (CDCl₃, 400 MHz) δ 1.0 (t, 6H), 1.5-1.7 (m, 4H), 1.95 (s, 3H),2.1 (s, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 3.95 (br, 1H), 4.1 (br, 1H), 6.9(s, 2H).

Example 3 PREPARATION OF3-ETHYL-[N-(1-ETHYL(PROPYL]-6-METHYL-5-(2,4,6-TRIMETHYLPHENYL)PYRAZINE-2-AMINE [Formula I: Ar=2,4,6-trimethylphenyl;R₂=—N(1-ETHYL(PROPYL; R₁=CH₂CH₃; R₃=CH₃]

[0171] N-butyllithium (2.5M in hexane, 0.24 mL) is added to a solutionof[N-(1-ETHYL(PROPYL]-3,6-dimethyl-5-(2,4,6-trimethylphenyl)pyrazine-2-amine(74 mg; 0.24 mmol) in THF (2 mL) at 0° C. After 10 minutes at 0° C.,iodomethane (0.020 mL) is added. The mixture is stirred at 0° C. for 10minutes, before being poured into aqueous ammonium chloride andextracted with Et₂O. The extract is dried (sodium sulfate), filtered,concentrated and the residue is purified by preparative TLC (10% EtOAcin hexane, developed 3 times) to give the title compound (17 mg): ¹H NMR(CDCl₃, 400 MHz) δ 1.0 (t, 6H), 1.25 (t. 3H), 1.5-1.7 (m, 4H), 1.95 (s,3H), 2.05 (s, 3H), 2.3 (s, 3H), 2.65 (q, 2H), 4.05 (m, 2H), 6.9 (s, 2H).

Example 4 PREPARATION OF3,6-DIETHYL-5-(2,4-DIMETHOXYPHENYL)-[N-(1-ETHYLPROPYL)]PYRAZINE-2-AMINE[Formula I: Ar=2,4-dimethoxyphenyl; R₂=—N(1-ETHYL(PROPYL; R₁=R₃=CH₂CH₃]

[0172] 2-Chloro-3,6-diethylpyrazine (Chem. Pharm. Bull. Jap.,27, 2027(1979)) is converted to the desired product following the proceduresdescribed in Example 1: ¹H NMR (CDCl₃, 300 MHz) δ 0.95 (t, 6H), 1.15 (t,3H), 1.25 (t, 3H), 1.5-1.7 (m, 4H), 2.45 (q, 2H), 2.65 (q, 2H), 3.75 (s,3H), 3.85 (s, 3H), 4.0-4.2 (br, 2H), 6.5 (s, 1H), 6.55 (d, 1H), 7.2 (d,1H).LC-MS: 358

Example 5 PREPARATION OF3,6-DIETHYL-5-(2,4-DIETHOXY)PHENYL-[N-(1-ETHYLPROPYL)]PYRAZINE-2-AMINE[Formula I: Ar=2,4-diethoxyphenyl; R₂=—N(1-ETHYL(PROPYL; R₁=R₃=CH₂CH₃]

[0173] A: BBr₃ is added to a solution of3,6-diethyl-5-(2,4-dimethoxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amine(910 mg, 2.54 mmol). (obtained in example 4) in dichloromethane (1N, 6ml) at −78° C. The mixture is stirred for 10 minutes, then graduallywarmed to room temperature and stirred for 3 hours before being pouredinto ice-water and extracted with dichloromethane. The aqueous layer isbasified with saturated NaHCO₃ and extracted with dichloromethane. Thecombined extracts are dried (sodium sulfate), filtered, concentrated andthe residue is purified by column chromatography (20% EtOAc in hexane)to give3,6-diethyl-5-(2,4-dihydroxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amineas a yellow oil (590 mg, 71%): ¹H NMR (CDCl₃, 400 MHz) δ 0.94 (t,6H),1.30(t,3H), 1.36(t,3H), 1.57(m,2H), 1.67(m,2H), 2.62(q,2H), 2.86(q,2H),4.15(m, 2H), 6.41(d,1H), 6.51(d,1H), 7.27(d,1H). LC-MS: 330 (M+1).

[0174] B: The above yellow oil (60 mg, 0.182 mmol) is dissolved in DMF(2 ml) and alkylated with iodoethane (0.072 ml, 0.9 mmol) in thepresence of K₂CO₃ (125 mg) at 75° C. for 2 hours. The reaction mixtureis then diluted with water and extracted with EtOAc. The extracts aredried (sodium sulfate), filtered, concentrated and the residue ispurified by column (2.5% MeOH in dichloromethane) to give the titlecompound as an oil (49 mg, 70%): ¹H NMR (CDCl₃, 400 MHz) δ 0.96 (t,6H),1.13(t,3H), 1.27(m,6H), 1.42(t,3H), 1.57(m,2H), 1.67(m,2H), 2.47(m,2H),2.66(q,2H), 3.95-4.15(m, 6H), 6.49(s,1H), 6.53(d,1H), 7.15(d,1H). LC-MS:387 (M+1).

Example 6 PREPARATION OF[N-(1-ETHYL(PROPYL]-5-(2-METHOXY-4,6-DIMETHYLPHENYL)-3,6-DIMETHYLPYRAZINE-2-AMINE[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂=N(1-ETHYL(PROPYL;R₁=R₃=CH₃]

[0175] A. 2-Methoxy-4,6-dimethylbenzeneboronic acid (1.08 g, 6.0 mmol)is added to a solution of 2-chloro-3,6-dimethylpyrazine (0.71 g, 5.0mmol) and tetrakis(triphenylphosphine) palladium(0) (140 mg, 2.5 mol %)in ethylene glycol dimethyl ether (30 mL), followed by the addition of 1M aqueous sodium carbonate solution (15 mL). The mixture is stirred at70-75° C. overnight, allowed to cool, diluted by saturated aqueoussodium bicarbonate solution, and extracted twice with Et₂O. Combinedextracts are dried (sodium sulfate), filtered, and concentrated invacuo. The residue is purified by filtration through a short pad ofsilica gel to give 1.4 g of crude product.

[0176] B. The crude material obtained in step A is dissolved indichloromethane (20 mL), cooled to 0° C. M-chloroperoxybenzoic acid(70%, 1.2 g) is added in portions. After 4 hours at ambient temperature,the mixture is diluted by n-hexane (20 mL) and washed with 1 M aqueoussodium hydroxide solution. The organic phase is separated, dried (sodiumsulfate), filtered, concentrated in vacuo, and the residue is useddirectly in the next step without further purification.

[0177] C. The crude N-oxide is dissolved in phosphorus oxychloride (10mL) and the solution is heated at 80° C. overnight. Evaporation ofphosphorus oxychloride and aqueous work-up of the residue followed bychromatography on silica yields 2-aryl-5-chloro-3,6-dimethylpyrazine asa white solid (0.76 g).

[0178] D. A 0.2 M solution of tri-tert-butylphosphine in toluene (0.10mL) is added to a solution of the chloropyrazine obtained in step C (260mg, 0.94 mmol) and tris(dibenzylideneacetone)dipalladium(0) (I 1 mg) intoluene (10 mL). After 15 minutes at ambient temperature,1-ethylpropylamine (0.14 mL) and potassium t-butoxide (1.0 M in THF, 1.4mL) are added successively and the reaction mixture is heated at 80° C.for 4 hours. The mixture is allowed to cool to room temperature, dilutedby ether, washed with aqueous ammonium chloride solution, dried (sodiumsulfate), filtered, concentrated, and chromatographed on silica to givethe desired product as a white solid (250 mg): ¹H NMR (CDCl₃, 400 MHz) δ0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.0 (s, 3H), 2.1 (s, 3H), 2.4 (s, 6H),3.7 (s,3H), 3.95 (br d, 1H), 4.1 (br q, 1H), 6.6 (s, 1H), 6.7 (s, 1H).

Example 7 PREPARATION OF5-(2-METHOXY-2,4-DIMETHYLPHENYL)-3,6-DIMETHYL-2-(3-PENTYLOXY)PYRAZINE[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂=—OCH(CH₂CH₃)₂;R₁=R₃=CH₃]

[0179] 3-Pentanol (0.1 mL) is added to a suspension of NaH (60% inmineral oil, 40 mg) in DMF (0.5 mL) The mixture is stirred at ambienttemperature until hydrogen evolution ceased. An N-methylpyrrolidinonesolution of 2-aryl-5-chloro-3,6-dimethylpyrazine (20 mg in 0.5 mLsolvent) is added to the resulting alkoxide solution. After 1 hour atroom temperature, the mixture is heated to 70° C. for another hourbefore being allowed to cool. The mixture is then diluted with aqueousammonium chloride solution and extracted twice with Et₂O. Combinedorganics are dried (sodium sulfate), filtered, concentrated, andchromatographed on silica gel to give the title compound as a colorlessoil (15 mg): ¹H NMR (CDCl₃, 400 MHz) δ 1.0 (t, 6H), 1.75 (m, 4H), 1.95(s, 3H), 2.15 (s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 3.7 (s, 3H), 5.1(quint, 1H), 6.6 (s, 1H), 6.7 (s, 1H): MS (CI) 329, 259.

Example 8 PREPARATION OF[N-(1-ETHYL(PROPYL]-3,6-DIMETHYL-5-{2-[2-(4-MORPHOLINO)ETHYL]OXY-4,6-DIMETHYLPHENYL}PYRAZINE-2-amine [Formula I:Ar-2-[2(4-morpholino)ethyl]oxy-4,6-dimethylphenyl; R₂=—NHCH(CH₂CH₃)₂;R₁=R₃=CH₃]

[0180] A. A solution of2-chloro-3,6-dimethyl-5-(2-methoxy-4,6-dimethylphenyl)pyrazine (180 mg)in dichloromethane is cooled to 0° C. and boron tribromide (0.1 mL) isadded slowly and dropwise. After the addition, the mixture is stirred at0° C. for an additional 1.5 hours, diluted by Et₂O, washed withsaturated aqueous sodium bicarbonate solution, dried (sodium sulfate),filtered, and concentrated in vacuo. The residue is used in the nextstep without further purification.

[0181] B. 4-(2-Chloroethyl)morpholine hydrochloride (200 mg) is added inone portion to a suspension of the crude phenol and potassium carbonate(400 mg) in DMF (4 mL) and the mixture is stirred at 60° C. for 4 hours.After further stirring at room temperature overnight, the mixture ispoured into aqueous sodium bicarbonate and extracted twice with Et₂Ohexane. Combined extracts are dried (sodium sulfate), filtered,concentrated, and chromatographed on silica (eluent 5% triethylamine in1:1 EtOAc-hexane) to give the product as a colorless oil (160 mg).

[0182] C. The chloropyrazine is converted to the correspondingaminopyrazine using methods:known in the art. ¹H NMR (CDCl₃, 400 MHz) δ0.95 (m, 6H), 1.6 (m, 4H), 2.0 (s, 3H), 2.1 (s, 3H), 2.3 (m, 4H), 2.35(s, 6H), 2.6 (m, 2H), 3.6 (m, 2H), 3.9 (d, 1H), 4.0 (m, 2H), 4.05 (m,1H), 6.55 (s, 1H), 6.7 (s, 1H); MS (CI) 427.

Example 9 PREPARATION OF 3-BROMO-6-CHLORO-5-(2,4-DICHLOROPHENYL)-[N-(15ETHYL(PROPYL]PYRAZINE-2-AMINE [Formula I: Ar=2,4-dichlorophenyl; R₁=Br;R₂=NHCH(CH₂CH₃)₂; R₃=Cl]

[0183] A. A solution of 2,6-dichloropyrazine (2.2g) and1-ethylpropylamine (5 mL) in EtOH (10 mL) is heated at 140° C. in aTeflon-sealed tube. The resulting solution is concentrated in vacuo,diluted by water, and extracted twice with hexane-ethyl ether. Combinedextracts are dried (sodium sulfate), filtered, concentrated in vacuo,and the residue is filtered through a short pad of silica gel. Thefiltrate is concentrated to give6-chloro-[N-(1-ETHYL(PROPYL]pyrazine-2-amine as brownish oil thatsolidifies on standing (3.0 g).

[0184] B. A solution of the above amine (4.09 g; 20.48 mmol) inchloroform (80 ml) is cooled to 0° C. and N-bromosuccinimide (3.65 g;20.48 mmol) is added in portions. The mixture is stirred at 0° C. for 30minutes, poured into saturated aqueous NaHCO₃, and extracted withdichloromethane. The combined extracts are washed successively withwater and brine, dried (sodium sulfate), and concentrated in vacuo. Theresidue is chromatographed on silica gel (6% EtOAc in hexane) to givethe desired 3-bromopyrazine as a minor product (0.53 g; 9%) along with6-chloro-5-bromo-[N-(1-ETHYL(PROPYL]pyrazine-2amine (4.37 g; 77%) as themajor isomer.

[0185] C. 5-bromopyrazine obtained as above undergoes Suzuki couplingwith 2,4-dichlorobenzeneboronic acid following the procedures in Example1C to give6-chloro-5(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amine.

[0186] D. The aryl pyrazine is brominated again by usingN-bromosuccinimide as described in Example 9B to give the desiredproduct: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.58 (m,2H), 1.70(m,2H), 4.00 (m,1H), 5.20 (d,1H), 7.30 (s, 2H), 7.50 (s,1H); MS(CI) 422.

Example 10 PREPARATION OF6-CHLORO-5-(2,4-DICHLOROPHENYL)-[N-(1-ETHYL)PROPYL]-3(2-PROPENYL)PYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁=CH₂CH=CH₂; R₂=—NHCH(CH₂CH₃)₂;R₃=Cl]

[0187] The bromopyrazine obtained in Example 9 is converted to thedesired product by using allylboronic acid following the procedure setforth in Example 1C: ¹H NMR (CDCl₃, 400 MHz) δ 0.93 (t, 6H), 1.50-1.71(m, 4H), 3.50 (d, 2H), 4.05 (m, 1H), 4.55 (d, 1H), 5.22 (m, 2H), 5.92(m, 1H), 7.34 (m, 2H), 7.48 (m, 1H); MS(CI) 384.

Example 11 PREPARATION OF6-CHLORO-5-(2,4-DICHLOROPHENYL)-3-ETHYL-[N-(1-ETHYL)PROPYL]PYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH₃; R₂═NHCH(CH₂CH₃)₂; R₃═Cl]

[0188] The bromopyrazine obtained in Example 9 is converted to thedesired product by using ethaneboronic acid following the same procedureas in Example 1C: ¹H NMR (CDCl₃, 400 MHz) δ 0.96 (t, 6H), 1.30 (t, 3H),1.56 (m, 2H), 1.70 (m, 2H), 2.65 (t, 2H), 4.08 (m, 1H), 4.35 (d, 1H),7.32 (d, 1H), 7.33 (s, H), 7.48 (d, 1H); MS (CI) 372.

Example 12 PREPARATION OF5-(2,4-DICHLOROPHENYL)-6-ETHYL-[N-(1-ETHYL)PROPYL]PYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁═H; R₂═NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0189] A. 6-chloro-[N-(1-ethyl)propyl]pyrazine-2-amine obtained inExample 9A reacts with ethylmagnesium bromide as in Example 2 to give6-ethyl-[N-(1-ethyl)propyl]pyrazine-2amine.

[0190] B. The 6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine obtained instep A is brominated and coupled with 2,4-dichlorobenzeneboronic acidfollowing the same procedure set forth in Examples 9B and 9C,respectively to give the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.97(t, 6H), 1.13 (t,3H), 1.56 (m,2H), 1.65 (m,2H), 2.45 (m,2H), 3.72(m,1H), 4.45 (d,1H), 7.25 (d, 1H), 7.30 (dd,1H), 7.48 (d,1H), 7.74(s,1H); MS(CI) 338.

Example 13 PREPARATION OF3-BROMO-5-(2,4-DICHLOROPHENYL)-6-ETHYL-[N-(1-ETHYL)PROPYL]PYRAZINE-2-AMINE[Formula I: Ar═2,4-dichlorophenyl; R₁═Br; R₂═NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0191] The product of Example 12 is brominated via the procedure givenin Example 9B to give the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.97(t, 6H), 1.14 (t, 3H), 1.56 (m, 2H), 1.65 (m, 2H), 2.45 (m, 2H), 4.02(m, 1H), 5.00 (d, 1H), 7.25 (d, 1H), 7.30 (dd, 1H), 7.46 (d, 1H); MS(CI) 416.

Example 14 PREPARATION OF5-(2,4-DICHLOROPHENYL)-6-ETHYL-[N-(1-ETHYL)PROPYL]-3-METHOXYPYRAZINE-2-AMINE.[Formula I: Ar=2,4-dichlorophenyl; R₁=OCH₃; R₂═NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0192] 3-Bromo-6-ethyl-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amine, obtained by the method given in the previous example,is added to a 1 N solution of sodium methoxide in N-methylpyrrolidinone.The mixture is heated to 70° C. for 6 hours before being allowed to cooland then diluted with water and extracted with 20% EtOAc in hexane. Thecombined extracts are washed with water, dried (sodium sulfate),filtered, concentrated in vacuo, and chromatographed on silica gel togive the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.12(t,3H), 1.56 (m, 2H), 1.65 (m, 2H), 2.40 (q, 2H), 3.92 (s, 3H), 4.04 (m,1H), 4.82 (d, 1H), 7.28 (m, 2H), 7.48 (d, 1H); MS(CI) 368.

Example 15 PREPARATION OF5-(2,4-DICHLOROPHENYL)-3-ETHYL-6-METHYL-[N-(1-ETHYL)PROPYL]PYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH₃; R₂═NHCH(CH₂CH₃)₂; R₃═CH₃]

[0193] A: [1,3-Bis(diphenylphosphino)propane]dichloronickel(II) (540 mg)is added to a solution of 2-(3-pentylamino)-6-chloropyrazine (4.26 g,21.3 mmol) in THF (30 mL) at room temperature. After 10 minutes,methylmagnesium bromide (3.0M in diethyl ether, 15.7 mL) is added slowlyand dropwise at 0° C. The mixture is stirred at room temperature for 1hour. The resulting dark solution is poured into aqueous ammoniumchloride and extracted twice with ether. Combined extracts are dried(sodium sulfate), filtered, concentrated, and chromatographed to givethe desired product as a light brown oil (98%).

[0194] B: A solution of the above oil in chloroform (60 mL) is cooled to0° C. and N-bromosuccinimide (3.8 g) is added in portions. After theaddition, the mixture is further stirred for 1 hour while being allowedto warm to room temperature. The mixture is then concentrated to a smallvolume in vacuo, triturated with hexane, filtered, and washed withhexane. The filtrate is concentrated and chromatographed on silica gel(8% ethyl acetate in hexane elution) to give5-bromo-[N-(1-ethyl)propyl]-6-methylpyrazine-2-amine (92%).

[0195] C. A mixed solution of the above bromide (1.2 g; 4.65 mmol) andtetrakis(triphenylphosphine)palladium(0) (4 mol %) in ethyleneglycoldimethyl ether (60 mL) is stirred at room temperature for 15 minutes.2,4-Dichlorobenzeneboronic acid (1.3 g, 7 mmol) and an aqueous solutionof sodium carbonate (1.0M, 12 mL) are then added sequentially. Themixture is heated to 75° C. with stirring for 1.5 hour, then dilutedwith 0.1N sodium hydroxide and extracted twice with 1:1 hexane-ethylether. Combined extracts are dried (sodium sulfate), filtered,concentrated, and chromatographed on silica (4:1 hexane-EtOAc) to give5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine as ayellow oil (1.46 g, 97%): ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t,6H),1.54(m,2H), 1.67(m,2H), 2.22(s,3H), 3.65(m,1H), 4.50(br, 1H),7.27(d,1H), 7.31(dd,1H), 7.48(d,1H), 7.76(s, 1H).

[0196] D: A solution of the above oil (1.27 g, 3.92 mmol) in chloroform(40 mL) is cooled to 0° C. and N-bromosuccinimide (770 mg) is added inportions. After the addition, the mixture is further stirred for 1 hourwhile being allowed to warm to room temperature. The mixture is thenconcentrated to a small volume in vacuo, triturated with hexane,filtered, and washed with hexane. The filtrate is concentrated andchromatographed on silica gel (3% ethyl acetate in hexane elution) togive3-bromo-5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine(1.56 g, 98%).

[0197] E: A mixed solution of3-bromo-5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine(960 mg; 2.38 mmol) and tetrakis(triphenylphosphine) palladium(0) (4 mol%) in ethyleneglycol dimethyl ether (25 mL) is stirred at roomtemperature for 15 minutes. Ethaneboronic acid (1.0 g) and an aqueoussolution of sodium carbonate (1.0M, 8.5 mL) are then added sequentially.The mixture is heated to 75° C. with stirring for 12 hours, then dilutedwith 0.1N sodium hydroxide and extracted twice with 1:1 hexane-ethylether. Combined extracts are dried (sodium sulfate), filtered,concentrated, and chromatographed on silica (10:1 hexane-EtOAc) to givethe title compound as a yellow oil (460 mg, 55%): ¹H NMR (CDCl₃, 400MHz) δ 0.95 (t, 6H), 1.28(t, 3H), 1.54(m, 2H), 1.67(m, 2H), 2.20(s, 3H),2.65(q, 2H), 4.13(m, 2H), 7.27(d, 1H), 7.31(d, 1H), 7.48(s, 1H).LC-MS:352 (M+1).

Example 16 PREPARATION OF5-(2,4-DICHLOROPHENYL)-3-ETHOXY-6-ETHYL-[N-(1-ETHYL)PROPYL]PYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁═OCH₂CH₃; R₂═—NHCH(CH₂CH₃)₂;R₃═CH₂CH₃]

[0198] The same reaction as in Example 15 with sodium ethoxide gives thetitle compound: ¹H NMR (CDCl₃, 400 MHz)) δ 0.95 (t, 6H), 1.10 (t, 3H),1.37 (t, 3H), 1.55 (m, 2H), 1.68 (m, 2H), 2.36 (m, 2H), 4.05 (m, 1H),4.33 (q, 2H), 4.81 (d, 1H), 7.24 (d, 1H), 7.26 (dd, 1H), 7.46 (d, 1H);MS(CI) 382.

Example 175-(2,4-DICHLOROPHENYL)-6-ETHYL-[N-(1-ETHYL)PROPYL]-3-METHYLPYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₃; R₂═NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0199] 3-Bromo-5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine obtained from Example 9 is converted to the titlecompound by using methylmagnesium bromide according to the procedure setforth in Example 2: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.12 (t,3H), 1.56 (m, 2H), 1.65 (m, 2H), 2.35 (s, 3H), 2.42 (m, 2H), 4.04 (m,2H), 7.25 (d, 1H), 7.29 (dd, 1H), 7.46 (d, 1H); MS (CI) 352.

Example 18 PREPARATION OF3-BROMO-5-(2,4-DICHLOROPHENYL)-[N-(1-ETHYL)PROPYL]-6-METHOXYPYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁=Br; R₂═NHCH(CH₂CH₃)₂; R₃═OCH₃]

[0200]6-Chloro-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amineobtained in Example 9C is converted to5-(2,4-dichlorophenyl)-6-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amineaccording to the procedure given in Example 16. The resulting amine isconverted to the title compound via the procedure given in Example 9: ¹HNMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.60 (m, 2H), 1.70 (m, 2H), 3.89(s, 3H), 3.92 (m, 1H), 4.98 (d, 1H), 7.27 (dd, 1H), 7.34 (d, 1H), 7.44(d, 1H); MS (CI) 418.

Example 195-(2,4-DICHLOROPHENYL)-[N-(1-ETHYL)PROPYL]-3,6-DIMETHOXYPYRAZINE-2AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁=R₃═OCH₃, R₂=—NHCH(CH₂CH₃)₂]

[0201] Sodium methoxide (3.0 mmole) is added to a solution of3-bromo-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine(0.8 mmole) in 1-methyl-2pyrrolidinone (5 ml). The resulting mixture isthen heated to 80° C. for three days. The mixture is diluted with waterand extracted with ethyl acetate. The combined extracts are washedthoroughly with water, and then brine, and dried. After removing thesolvent, the crude is purified by silica gel column (eluted with 3%EtOAc in hexane) to give the title compound as a light yellow oil (65%yield). ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.56 (m, 2H), 1.68 (m,2H), 3.86 (s, 3H), 3.94 (s,3H), 3.95(m, 1H), 4.82 (d, 1H), 7.27 (dd,1H), 7.40 (d, 1H), 7.44 (d, 1H). MS (CI) 370.

Example 20 PREPARATION OF3-ETHYL-5-(2,4-DICHLOROPHENYL)-[N-(1-ETHYL)PROPYL]-6-METHOXYPYRAZMNE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁=CH₂CH₃; R₃═OCH₃,R₂=—NHCH(CH₂CH₃)₂]

[0202] A: A solution of sodium methoxide in methanol (5.0M, 10 ml) I sadded to a solution of 2-(3-pentylamino)-6-chloropyrazine (3.3 g, 16.5mmol) in 1-methyl-2-pyrrolidinone (15 mL) at room temperature. Theresulting solution is heated to 50° C. for 20 hours then evaporated andpoured into water and extracted twice with ethyl acetate/hexane (1:1).Combined extracts are dried (sodium sulfate), filtered, concentrated,and chromatographed to give N-(1-ethyl)propyl-6-methoxypyrazine-2-amineas a light yellow solid (98%).

[0203] B: A solution of the above solid in chloroform (60 mL) is cooledto 0° C. and N-bromosuccinimide (3.0 g) is added in portions. After theaddition, the mixture is further stirred for 1 hour while being allowedto warm to room temperature. The mixture is then diluted withdichloromethane, washed with saturated NaHCO₃, water, and brine, andthen dried and filtered. The filtrate is concentrated andchromatographed on silica gel (dichloromethane/hexane 1:1 elution) togive 3-bromo-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine as a yellowoil (35%). ¹H NMR (CDCl₃, 400 MHz) δ 0.93 (t, 6H), 1.56 (m, 2H), 1.66(m, 2H), 3.87 (s, 3H), 3.92(m, 1H), 4.85 (d, 1H), 7.18 (s, 1H).

[0204] C: To a solution of above3-bromo-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine (1.27 g, 4.63mmol) in THF (30 mL) is added [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (125 mg). After 10 minutes, ethylmagnesium bromide(1.0M in THF, 9.7 mL) is added slowly and dropwise at 0° C. The mixtureis stirred at room temperature for 1 hour. The resulting dark solutionis poured into aqueous ammonium chloride and extracted twice with ether.Combined extracts are dried (sodium sulfate), filtered, concentrated,and chromatographed (2.5% MeOH/CH₂Cl₂) to give the desired product3-ethyl-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine as a light yellowoil (55%).

[0205] D: A solution of the above oil (0.55 g, 2.46 mmol) in chloroform(10 mL) is cooled to 0° C. and N-bromosuccinimide (445 mg) is added inportions. After the addition, the mixture is r stirred for anadditional30 minutes while being allowed to warm to room temperature.The mixture is then concentrated to dryness in vacuo, andchromatographed on silica gel (5% ethyl acetate in hexane elution) togive 5-bromo-3-ethyl-6-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amine(85%).

[0206] E. A mixed solution of the above bromide (100 mg; 0.33 mmol) andtetrakis (triphenylphosphine)palladium(0) (5 mol %) in ethyleneglycoldimethyl ether (3 mL) is stirred at room temperature for 15 minutes.2,4-Dichlorobenzeneboronic acid (95 mg) and an aqueous solution ofsodium carbonate (1.0M, 0.75 mL) are then added sequentially. Themixture is heated to 75° C. with stirring for 15 hoys, then diluted withwater and extracted twice with 1:1 hexane-ethyl ether. Combined extractsare dried (sodium sulfate), filtered, concentrated, and chromatographedon silica (6% ethyl acetate in hexane) to give the title compound as ayellow oil (121 mg, 99%): ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t,6H),1.27(t,3H), 1.56(m,2H), 1.70(m,2H), 2.62(q,2H), 3.85(s,3H), 4.00(m, 1H),4.18 (d,1H), 7.28(d,1H), 7.38(d,1H), 7.44(s,1H). MS: 368.

Example 21 PREPARATION OF3-ETHYL-5-(2-METHOXY-4-TRIFLUOROMETHOXYPHENYL)-[N(1-ETHYL)PROPYL]-6-METHOXYPYRAZINE-2-AMINE

[0207]

[0208] A. (1-Ethyl-propyl)-(3-ethyl-pyrazin-2-yl)-amine. In a pressuretube, 2-chloro-3-ethyl-pyrazine (1.4 g, 10 mmol), Pd₂(dba)₃ (229 mg,0.25 mmol) and P(t-Bu)₃ (100 microliters, 0.4 mmol) are dissolved intoluene (15 mL) and stirred at room temperature for 30 minutes.1-Ethyl-propylamine (1.75 mL, 15 mmol) and KOt-Bu (1M in THF, 15 mmol,15 mL) are added, and the dark solution is stirred at 55° C. (oil bathtemperature) for 90 minutes. The reaction mixture is allowed to reachroom temperature, diluted with ethyl ether (100 mL) and washed withbrine (3×100 mL). After drying with MgSO₄, the solvents are removedunder reduced pressure. A dark oil is obtained. Flash chromatography(100% hexanes to 20% ethyl acetate in hexanes) produces the desiredproduct (710 mg, 37%). H-1 NMR (CDCl₃, 300 MHz): 7.84 (1H, d, J=8.1 Hz),7.68 (1H, d, J=9 Hz), 4.15 (br, 1H), 4.05 (quint, 1H), 2.6 (2H, q, J=7.4Hz), 1.4-1.6 (m, 4H), 1.32 (t, 3H, J=7.4 Hz), 0.95 (t, 6H, J=7.4 Hz).MS: 194 (M+1, positive mode) and 192 (M−1, negative mode).

[0209] B. (5-Bromo-3-ethyl-pyrazin-2-yl)-(1-ethyl-propyl)-amine. Theproduct from step A (650 mg, 3.4 mmol) is dissolved in chloroform (20mL) and treated at room temperature with N-bromosuccinimide (600 mg, 3.5mmol). After 5 minutes the mixture is diluted with chloroform (100 mL)and the organic solution washed with brine (3×100 mL), dried (MgSO₄),filtered, and the solvent removed under reduced pressure to produce5-bromo-3-ethyl-pyrazin-2-yl)-(1-ethyl-propyl)-amine (700 mg, 77%). H-1NMR (CDCl₃, 400 MHz): 7.94 (1H, s), 4.1 (br, 1H), 3.95 (quint, 1H), 2.60(2H, q, J=7.4 Hz), 1.4-1.6 (m, 4H), 1.32 (t, 3H, J=7.4 Hz), 0.95 (t, 6H,J=7.4 Hz). MS: 274.1 (M+1, positive mode) and 270.3 (M−1, negativemode).

[0210] C.[3-Ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)amine.In a pressure tube, a mixture of the product from step B (700 mg, 2.6mmol), 2methoxy-4-trifluoromethoxyboronic acid (1.0 g, 4.2 mmol) andPd(PPh₃)₄ (100 mg) in toluene (10 mL), ethanol (0.5 mL), and aqueousK₂CO₃ (2M, 5 mL) is heated in oil bath at 80° C. for 16 hours. Themixture is diluted with ethyl acetate, and the organic fraction washedwith NaOH (2M, 50 mL) and brine (3×50 mL), dried (MgSO₄) filtered, andthe solvent removed under reduced pressure. Flash chromatography of theresidue (100% hexanes to 4% ethyl acetate in hexanes) provides thedesired product as an oil (850 mg, 85%). ¹H NMR (CDCl₃, 300 MHz): 8.53(1H, s), 7.91 (1H, d, J=8.8 Hz), 6.93 (1H, d, J=8.8 Hz), 6.80 (s, 1H),4.18 (1H, d, J=8.2 Hz), 4.10 (quint, 1H, J=5.8 Hz), 3.88 (3H, s), 2.6(2H, q, J=7.4 Hz), 1.4-1.6 (m, 4H), 1.37 (t, 3H, J=7.4 Hz), 0.95 (t, 6H,J=7.4 Hz). MS: 384.3 (M+1, positive mode) and 382.2 (M−1, negativemode).

[0211] D.[3-Ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-4-oxy-pyrazin-2-yl]-(1-ethyl-propyl)-amine.The aminopyrazine obtained in step C (370 mg, 0.97 mmol) is dissolved indichloromethane (15 mL) and treated with solid m-chloroperoxybenzoicacid (374 mg, 1.3 eq) at room temperature. After 3 hour the reactionmixture is diluted with dichloromethane (50 mL) and washed with NaOH 2M(25 mL) and brine (3×50 mL). The organic solution is dried (MgSO₄),filtered and the solvent evaporated under reduced pressure. The residueis purified by preparative thin layer chromatography, eluting with 30%ethyl acetate in hexanes), to furnish the desired product (55 mg, 14%).NMR (CDCl₃, 400 MHz) H-1: 7.86 (1H, s), 7.38 (1H, d, J=8.4 Hz), 6.89(1H, d, J=7.2 Hz), 6.81 (s, 1H), 4.21 (1H, d, J=8.0 Hz), 4.08 (quint,1H, J=6.0 Hz), 3.81 (3H, s), 2.9 (2H, q, J=7.6 Hz), 1.5-1.75 (m, 4H),1.23 (t, 3H, J=7.2 Hz), 0.96 (t, 6H, J=7.6 Hz). C-13: 158.96, 154.43,150.64, 142.56, 132.86, 132.47, 131.32, 119.15, 112.22, 104.58, 104.58,56.01, 53.35, 26.96, 17.89, 10.04, 8.86. F-19 NMR: −58.04 (s). (MS:400.3 (M+1, positive mode) and 398.3 (M−1, negative mode).

[0212] E.[6-Chloro-3-ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethylpropyl)-amine.The N-oxide from step D (40 mg, 0.11 mmol) is dissolved in POCl₃ (1.5mL) and heated at 80° C. for 16 hours. After cooling to roomtemperature, the reaction mixture is diluted with ethyl ether (100 mL),washed with NaOH (2M, 50 mL) and brine (3×50 mL), dried (MgSO₄),filtered, and the solvent evaporated under reduced pressure to affordthe desired chloropyrazine (40 mg, 96%). NMR (CDCl₃, 400 MHz) H-1: 7.32(1H, d, J=8.4 Hz), 6.89 (1H, d, J=7.2 Hz), 6.80 (s, 1H), 4.26 (1H, d,J=8.4 Hz), 4.07 (quint, 1H, J=5.6 Hz), 3.82 (3H, s), 2.64 (2H, q, J=7.6Hz), 1.5-1.75 (m, 4H), 1.29 (t, 3H, J=7.6 Hz), 0.96 (t, 6H, J=7.2 Hz).C-13: 158.20, 150.91, 150.14, 143.80, 140.95, 134.30, 131.94, 126.07,112.44, 104.58, 55.78, 53.01, 26.81, 25.75, 10.80, 10.02. F-19 NMR:−58.03 (s). (MS: 418.2 (M+1, positive mode) and 416.2 (M−1, negativemode).

[0213] F.[3-Ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine.In a pressure tube, the chloropyrazine from step E (30 mg) is dissolvedin DMF (2 mL) and treated with sodium methoxide (100 mg) at 80° C. for120 hours. The reaction mixture is diluted with ethyl ether (50 mL) andwashed with brine. The residue is purified by preparative thin layerchromatography (15% ethyl acetate in hexanes to produce[3-ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethylpropyl)-amine(10 mg, 33%).

Example 22 6-CHLORO-[N-(1-ETHYL)PROPYL]-3-METHOXY-5-(2,4-DICHLOROPHENYL)PYRAZINE-2-AMINE [Formula I: Ar-2,4-dichlorophenyl; R₁═OCH₃;R₂=—NHCH(CH₂CH₃)₂; R₃=Cl]

[0214] A. A solution in DMF (2 mL) of3-bromo-6-chloro-[N-(1-ethyl)propyl]pyrazine-2amine (0.50 g; 1.8 mmol)obtained as a minor product in Example 9B is added into a solution ofsodium methoxide (freshly prepared from 90 mg of sodium metal inmethanol; 3.9 mmol) in DMF (3 mL). The mixture is stirred at roomtemperature overnight, then poured into aqueous ammonium chloridesolution and extracted twice with hexane-ethyl ether. Combined extractsare dried (sodium sulfate), filtered, concentrated in vacuo, andchromatographed on silica gel to give6-chloro-3-methoxy-[N-(1-ethyl)propyl]pyrazine-2amine (410 mg).

[0215] B. The above material is brominated according to via procedureused in Example 13 and converted to the title compound by the Suzukicoupling procedure disclosed in Example 1C: ¹H NMR (CDCl₃, 400 MHz) δ0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s, 3H), 3.8 (s, 3H), 3.85 (s, 3H),3.95 (s, 3H), 4.0 (m, 1H), 4.8 (br d, 1H), 6.55 (s, 1H), 6.55 (d, 1H),7.3 (d, 1H).

Example 23 PREPARATION OF5-(2,4-DICHLOROPHENYL)-[N-(1-ETHYL)PROPYL]-3-METHOXY-6-METHYLPYRAZINE-2-AMINE[Formula I: Ar=2,4-dichlorophenyl; R₁=OCH₃; R₂═NHCH(CH₂CH₃)₂; R₃═CH₃]

[0216] A. 6-chloro-3-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amineobtained in Example 22A is converted to the 6-methyl derivative andfurther brominated according to the same procedure used in Example 17.

[0217] B. The 5-bromopyrazine obtained in step A is converted to thetitle compound by the procedure used in Example 1C: ¹H NMR (CDCl₃, 400MHz) δ 0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s, 3H), 3.9 (s, 3H), 4.05(m, 1H), 4.8 (br d, 1H), 7.3 (s, 2H), 7.45 (s, 1H); MS (CI) 356.

Example 24 PREPARATION OF{4-[6-ETHYL-5-(ETHYLPROPOXY)-3-METHOXYPYRAZIN-2-YL]-3-METHOXYPHENOXY}TRIFLUOROMETHANE

[0218]

[0219] A. 4-methoxybenzylamine (68.6 g, 0.5 mol) is added to a stirredsolution of 2,6-dichloropyrazine (25 g, 0.167 mol) and ethanol (120 mL)in a sealed tube. The mixture is heated to 115 C for 12 hours andcooled. The white solid is removed by filtration and the filtrateevaporated. The residue is dissolved in ethyl acetate and washedsuccessively with 2M sodium hydroxide, water and aqueous sodiumchloride. The organics are dried (magnesium sulfate), filtered, andevaporated to give (6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine(35.5 g), a white solid.

[0220] B. Sodium methoxide (7.50 g, 125.0 mmol) is added to a stirredsolution of (6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (5.0 g,20.0 mmol) in DMF (30 mL). The mixture is heated at reflux for 12 hours,cooled and partitioned between ethyl acetate (100 mL) and water (100mL). The layers are separated and the organic layer washed with water(3×100 mL). The combined extracts are dried (magnesium sulfate),filtered, and evaporated to give[(4-methoxyphenyl)methyl](6-methoxypyrain-2-yl)amine (4.65 g), a yellowsolid.

[0221] C. A solution of[(4-methoxyphenyl)methyl](6-methoxypyrain-2-yl)amine (2.45 g, 10.0 mmol)in chloroform (50 mL) is cooled to 0 C and N-bromosuccinimide (1.8 g,10.0 mmol) is added in portions. After the addition, the mixture isfurther stirred for 1 hour while being allowed to warm to roomtemperature. The mixture is washed with saturated aqueous sodiumbicarbonate, aqueous sodium chloride, dried (magnesium sulfate),filtered and evaporated. The residue is purified by flashchromatography, eluting with 20% ether in hexanes to give(5-bromo-6-methoxypyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (1.1 g).

[0222] D. Tetrakis(triphenylphosphine)palladium(0) (100 mg) andpotassium carbonate (2.0 M, 2.0 mL) are added to a stirred solution of(5-bromo-6-methoxypyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (0.80 g,2.50 mmol) and 2-methoxy-4-trifluoromethoxy benzeneboronic acid (1.75 g,7.5 mmol) in toluene (25 mL). The mixture is heated to 85 C for 8 hours,cooled to room temperature, diluted with 2.0 M sodium hydroxide andextracted twice with 1:1 hexane-ethyl ether. The combined extracts aredried (sodium sulfate), filtered and concentrated. The residue ispurified by flash chromatography, eluting with 60% hexanes in ether togive {6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2yl}[(4-methoxyphenyl)methyl]amine (967 mg).

[0223] E. A solution of{6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2yl}[(4-methoxyphenyl)methyl]amine(870 mg, 2.0 mmol) in chloroform (10 mL) is cooled to 0 C andN-bromosuccinimide (356 mg, 2.0 mmol) is added in portions. After theaddition, the mixture is further stirred for 1 hour while being allowedto warm to room temperature. The mixture is washed with saturatedaqueous sodium bicarbonate, aqueous sodium chloride, dried (magnesiumsulfate), filtered, and evaporated to give{3-bromo-6-methoxy-5-[2methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (920 mg), a yellow solid.

[0224] F. Tetrakis(triphenylphosphine)palladium(0) (50 mg) and potassiumcarbonate (2.0 M, 1.0 mL) are added to a stirred solution of{3-bromo-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)pbenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine(514 mg, 1.0 mmol) and ethylboronic acid (219 mg, 3.0 mmol) in toluene(8 mL). The mixture is heated to 85 C for 8 hours, cooled to roomtemperature, diluted with 2.0 M sodium hydroxide and extracted twicewith 1:1 hexane-ethyl ether. The combined extracts are dried (sodiumsulfate), filtered and concentrated. The residue is purified by flashchromatography, eluting with 20% ether in hexanes to give{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine(430 mg).

[0225] G. 1M hydrochloric acid in ether (2 mL) and 10% palladium oncarbon (40 mg) are added to{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (115 mg, 0.25 mmol) in methanol (3 mL)under a nitrogen atmosphere. The mixture is then hydrogenated at 1 ATMfor 18 hours, filtered through Celite and evaporated to give3-ethyl-6-methoxy-5-[2-methoxy-4(trifluoromethoxy)phenyl]pyrazin-2-ylamine(80 mg).

[0226] H. A solution of sodium nitrite (21 mg, 0.3 mmol) in water (1 mL)is added to a stirred solution of3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2ylamine(86 mg, 0.25 mmol) in 48% hydrogen bromide (0.3 mL) at 0 C. After 1.5hours copper bromide (43 mg, 0.3 mmol) is added and the mixture heatedto 70 C for 1 hour. The mixture is cooled to room temperature andextracted with ether. The extracts are dried (sodium sulfate), filteredand concentrated to give[4-(5-bromo-6-ethyl-3-methoxypyrazin-2yl)-3-methoxyphenoxy]trifluoromethane(76 mg).

[0227] 1.60% Sodium hydride (12 mg, 0.3 mmol) is added to a stirredsolution of 3-pentanol (88 mg, 1 mmol) in THF (1 mL). After 0.5 hours[4-(5-bromo-6-ethyl-3-methoxypyrazin-2yl)-3-methoxyphenoxy]trifluoromethane(41 mg, 0.1 mmol) is added. The mixture is heated to 50 C for 12 hours,cooled and partitioned between ethyl acetate and water. The organiclayer is washed with water, brine, dried (sodium sulfate), filtered andconcentrated. The residue is purified by preparative TLC eluting with50% ether in hexanes to give{4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane,a colorless oil (19 mg). NMR (CDCL3, 400 MHz) δ 0.98 (t, 6H), 1.22 (t,3H), 1.78 (m, 4H) 2.80 (q, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 5.05(quintet, 1H), 6.8 (s, 1H), 6.90 (d, 1H), 7.37 (d, 1H); MS 345 (M+1).

Example 25 SYNTHESIS OF[3-ETHYL-5-(2-METHOXY-4-TRIFLUOROMETHOXY-PHENYL)-6-METHYLSULFANYL-PYRAZIN-2-YL]-(1-ETHYL-PROPYL)-AMINE.

[0228]

[0229][6-chloro-3-ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethylpropyl)-amine(100 mg) is combined in a pressure tube equipped with Teflon O-ring,with NaSMe (200 mg), THF (5 mL) and DMF (3 mL). The mixture is heated at80° C. (oil bath temperature) for 72 hours. The crude mixture is dilutedwith ethyl acetate (40 mL) and water (40 mL), and the organic phasewashed with brine (3×100 mL). After drying (MgSO₄), filtration, andelimination of solvents at reduced pressure, the title compound isisolated as a clear oil by preparative thin layer chromatography (10%EtOAc in hexanes). Yield: 50 mg (49%). NMR (CDCl₃, 400 MHz) H-1: 7.32(1H, d, J=8.4 Hz), 6.88 (1H, m), 6.78 (s, 1H), 4.18 (1H, d), 4.07 (m,1H), 3.78 (3H, s), 2.64 (2H, q), 2.24 (s, 3H), 1.5-1.75 (m, 4H), 1.25(t, 3H), 0.96 (t, 6H). MS: 430.2 (M+1, positive mode) and 428.4 (M−1,negative mode).

Example 26 PREPARATION OF2-SEC-BUTYLSULFANYL-5-(2,4-DIMETHOXY-PHENYL)-3,6-DIETHYL-PYRAZINE

[0230]

[0231] NaH (60 mg, 1.5 mmol. 60% in mineral oil) is added to a solutionof butane-2-thiol (170 μL, 1.5 mmol) in THF (5 mL). After 10 minutes,2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (100 mg, 0.33mmol) in THF (1 mL) is added dropwise, and the mixture heated at 80° C.(oil bath temperature) for 16 hours. After extractive work-up,preparative thin layer chromatography (hexanes) furnishes the titlecompound as a clear oil (60 mg, 51%). NMR (CDCl₃, 400 MHz) H-1: 7.19(1H, d, J=8.4 Hz), 6.58 (1H, dd, J=2.4, 8.4 Hz), 6.60 (s, 1H, J=2.4 Hz),3.99 (sext, 1H, J=6.8 Hz), 3.85 (3H, s), 3.75 (3H, s), 2.81 (2H, q,J=7.4 Hz), 2.58 (2H, br q, J=6.8 Hz), 1.6-1.9 (m, 4H), 1.44 (3H, d,J=6.4 Hz), 1.28 (t, 3H, J=7.6 Hz), 1.19 (3H, t, J=7.6 Hz), 1.06 (t, 3H,J=7.2 Hz). C-13: 161.10, 157.86, 153.49, 151.79, 151.67, 144.47, 131.68,121.18, 104.78, 98, 60, 55.44, 55.33, 40.87, 29.65, 27.54, 27.08, 20.56,12.43, 12.09, 11.51. MS: 414.2 (+1, positive mode) and 412.2 (M−1,negative mode).

Example 27 PREPARATION OF1-[3,6-DIETHYL-5-(2-METHYLBUTYL)PYRAZIN-2-YL]-2,4-DIMETHOXYBENZENE

[0232]

[0233] A solution of 9-BBN (9-borabicyclo[3.3.1]nonane) in THF (0.5 M,6.0 mL, 3.0 mmol) is added to a solution of 2-methyl-1-butene (210 mg,3.0 mmol) in THF. The mixture is heated at reflux, under a nitrogenatmosphere for 12 hours and cooled.1-(5-Bromo-3,6-diethylpyrazin-2-yl)-2,4-dimethoxybenzene (664 mg, 2.0mmol), tetrakis(triphenylphosphine) palladium(0) (50 mg), and sodiumhydroxide (3.0 M, 3.0 mL, 3.0 mmol) are added to the solution. Themixture is heated at 50 C for 12 hours and cooled. 30% Hydrogen peroxide(1 mL) is added, the solution stirred for 1 hour and the reactionmixture extracted with ether. The combined extracts are dried (sodiumsulfate), filtered and concentrated. The residue is purified by flashchromatography, eluting with 40% ether in hexanes to give1-[3,6-diethyl-5-(2-methylbutyl)pyrazin-2-yl]-2,4-dimethoxybenzene (393mg).

Example 28 PREPARATION OF2-(2-METHOXY-5-TRIFLURORMETHOXYPHENYL)-3-ETHYL-6-METHYLAMINO-5-(1-ETHYLPROPOXY)-PYRAZINE

[0234]

[0235] A. A solution of6-(Chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine in chloroform (4mL/mmol NBS) is cooled to 0° C. and N-bromosuccinimide (1.05 eq) isadded in portions while stirring the reaction mixture. After completeaddition, the mixture is stirred for an additional hour while beingallowed to warm to room temperature. The mixture is then diluted withdichloromethane, washed with saturated NaHCO₃, water, and brine, andthen dried and filtered. The filtrate is concentrated and purified bychromatography on silica gel to give(5-bromo-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.

[0236] B. In a pressure tube, a mixture of the product from step A (1equivalent), 210 methoxy-5-trifluoromethoxyphenylboronic acid (1.6equivalents) and Pd(PPh₃)₄ (0.04 equivalents) in toluene (4 ml/mmol ofproduct from step A), ethanol (0.2 ml/mmol of product from step A) andaqueous K₂CO₃ (2M, 2 ml/mmol of product from step A) is heated to 80° C.for 16 hours. The mixture is diluted with ethyl acetate, and the organicfraction washed with NaOH (2M, 20 mL/mmol of product from step A) andbrine (3×20 ml/mmol of product from step A), then dried (MgSO₄),filtered and the solvent removed under reduced pressure. Chromatographyof the residue provides(3-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.

[0237] C.(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aaminecan be prepared by the method of Example 1, step A by substituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor 2-chloro-3,6-dimethylpyrazine.

[0238] D.(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)amine can beprepared by the hydrogentation method of Example 24, step G bysubstituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine.

[0239] E. 2-Bromo-5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be prepared by the halogenation method of Example 24, step H, bysubstituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)amine for{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl} amine.

[0240] F.2-(3-Pentoxy)-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be prepared by the method of Example 24, step I by substituting2-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor[4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane.

[0241] G.2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be prepared by the method of step A of the present Example bysubstituting2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinefor (6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.

[0242] H. Methylamine (1.2 equivalents) followed by sodium tert-butoxide(1.5 equivalents) is added to a mixture of2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazine(1 equivalent), tris(dibenzylideneacetone)dipalladium(0) (2 mol %), and1,1′-binaphthyl-2,2′-di(diphenylphosphine) (BINAP) (6 mol %) inethyleneglycol dimethyl ether (2.4 mL/mmol substrate) under nitrogen.The mixture is stirred at 70-80° C. for about 2.5 hours, diluted withaqueous ammonium chloride, and extracted with 1:1 hexane-diethyl ether.The combined extracts are dried (sodium sulfate), filtered, concentratedand then purified by chromatography on silica gel to afford2-(3-Pentoxy)-3-(N-methylamino)-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazine.

Example 29 ADDITIONAL COMPOUNDS OF FORMULA I

[0243] The following compounds, shown in Tables I, II, and III wereprepared using the methods shown in above Schemes I-IV, and furtherillustrated by Examples 1-28. Compounds shown in Table III each have aK_(i)<1 μm TABLE I CMP # STRUCTURE IUPAC NAME Ki < 1 μM 1

[5-(5-Ethyl-6-methoxy-2-methyl- pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)- amine * 2

N-5,N-5′-Bis-(1-ethyl-propyl )-6,6′- dimethoxy-3,3′-dimethyl-[2,2′]bipyrazinyl-5,5′-diamine * 3

[5-Methyl-6-(5-ethyl-6-methoxy-2- methyl-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 4

[5-Ethyl-6-(5-ethyl-6-methoxy-2- methyl-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 5

[6-(3,5-Dimethyl-isoxazol-4-yl)-5- ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 6

[5-Ethyl-6-(2-ethyl-6-isopropoxy-2- pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 7

[5-Ethyl-6-(2-ethoxy-6-isopropoxy- 2-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 8

[5-Ethyl-6-(2-methyl-6-isopropyl-2- pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 9

[5-Ethyl-6-(2-hydroxy-6-isopropyl- 2-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 10

[5-Ethyl-6-(2-methyl-6- dimethylamino-2-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]- methyl-amine * 11

[5-Ethyl-6-(2-dimethylamino-6- isopropyl-2-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 12

[6-(2-methyl-6-isopropyl-pyridin-3- yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine * 13

[6-(2-Azetidin-1-yl-6-isopropyl- pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 14

[6-(2-Diethylamino-6-isopropyl- pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 15

[3-(1-Ethyl-propoxy)-6-(6-isopropyl amino-2-methyl-5-bromo-pyridin-3-yl)-5-bromo-pyrazin-2-yl]- methyl-amine * 16

[6-(6-Dimethylamino-5-ethyl-2- methyl- pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine * 17

[3-(1-Ethyl-propoxy)-6-(6-isopropyl amino-2,5-dimethyl-pyridin-3-yl)-5-methyl-pyrazin-2-yl]-methyl-amine *

[0244] TABLE II CMP # STRUCTURE IUPAC NAME 18

5-ethyl-6-(1-ethylpropoxy)-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 19

5-bromo-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 20

3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2- amine 21

2-(4-tert-butyl-2-methoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine22

2-(4-tert-butyl-2-methoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 23

2,5-diethyt-3-(1-ethylpropoxy)-6-(4-isopropyl-2- methoxyphenyl)pyrazine24

2,5-diethyl-3-(4-isopropyl-2-methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 25

2-(2,6-dimethoxypyridin-3-yl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 26

2-(2,6-dimethoxypyridin-3-yl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 27

2,5-diethyl-3-(4-ethyl-2-methoxyphenyl)-6-(1- ethylpropoxy)pyrazine 28

2-[2-chloro-4-(difluoromethoxy)phenyl]-3,6-diethyl-5-(1-propylbutoxy)pyrazine 29

2,5-diethyl-3-(1-ethylbutoxy)-6-(4-isopropyl-2- methoxyphenyl)pyrazine30

2,5-diethyl-3-(1-ethylpropoxy)-6-(2-fluoro-4,6- dimethoxyphenyl)pyrazine31

2,5-diethyl-3-(2-fluoro-4,6-dimethoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 32

2,5-diethyl-3-(4-isopropyl-2-methoxyphenyl)-6-(1- propylbutoxy)pyrazine33

5-(1-ethylpropoxy)-2-[2-methoxy-4-(trifluoromethoxy)phenyl]-3-methylpyrazine 34

2-chloro-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methylpyrazine 35

2-(1-ethylpropoxy)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazine 36

6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine 37

5-[3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazin-2-yl]-6-methoxy-N,N- dimethylpyridin-2-amine 38

5-bromo-6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-1-ethylpropoxy)-N-methylpyrazin-2-amine 39

2-chloro-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-5-methylpyrazine 40

3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine 41

5-(1-ethylpropoxy)-2-[2-methoxy-4-(trifluoromethyl)phenyl]-3-methylpyrazine 42

5-bromo-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 43

2-chloro-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methylpyrazine 44

3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2- amine 45

3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethylpyrazin-2- amine 46

5-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 47

6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 48

5-bromo-6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine 49

6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine 50

5-bromo-6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 51

6-(4-ethoxy-2-methoxy-5-methylphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine 52

5-bromo-6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine 53

5-bromo-6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 54

5-bromo-3-ethoxy-6-(4-ethoxy-2-methoxyphenyl)-N- methylpyrazin-2-amine55

6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine 56

6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N- methylpyrazin-2-amine57

6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethyipropoxy)-N,5-dimethylpyrazin-2-amine 58

5-bromo-6-(4-ethoxy-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 59

6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N- methylpyrazin-2-amine60

5-bromo-3-(1-ethylbutoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine 61

6-(4-ethoxy-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 62

5-bromo-6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine 63

6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine 64

6-(4-ethoxy-2-methoxy-5-methylphenyt)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine 65

5-bromo-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methylpyrazin-2-amine 66

5-bromo-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 67

3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethylpyrazin-2- amine 68

6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 69

5-bromo-3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine 70

3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine 71

3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N,5-dimethylpyrazin-2-amine 72

5-ethyl-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N-methylpyrazin-2-amine 73

3-(1-ethylbutoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine 74

6-(2-ethyl-4-methoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile 75

6-(2,4-dimethoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile 76

5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 77

6-[2-chloro-4-(trifluoromethyl)phenyl]-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile 78

6-(2,6-dimethoxypyridin-3-yl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile 79

3-[(1-ethylpropyl)amino]-6-mesityl-5-methylpyrazine- 2-carbonitrile 80

6-(4-chloro-2,6-dimethoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile 81

3-[(1-ethylpropyl)amino]-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methylpyrazine-2- carbonitrile 82

5-[2-chloro-4-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 83

5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 84

5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine 85

5-bromo-6-(2-chloro-4-isopropoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 86

5-bromo-6-(2-chloro-4-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 87

6-(2-chloro-4-methoxyphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine 88

6-(2-chloro-4-isopropoxyphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine 89

N-(1-ethylpropyl)-5-mesityl-3-methoxy-6- methylpyrazin-2-amine 90

5-[6-(dimethylamino)-2,4-dimethylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 91

3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methylphenyl)-N,5-dimethylpyrazin-2-amine 92

5-bromo-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methylpyrazin-2-amine 93

N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxypyrazin-2-amine 94

5-bromo-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N-methylpyrazin-2-amine 95

5-bromo-6-(2-chloro-4-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 96

6-(2-chloro-4-methoxyphenyl)-5-ethyl-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 97

5-bromo-6-(2-chloro-4-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine 98

6-(2-chloro-4-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 99

2,5-diethyl-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yI)pyrazine 100

3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2- amine 101

3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 102

5-bromo-3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 103

3-{[(1R)-1-ethytbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2- amine 104

3-{[(1R)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine 105

5-bromo-3-{1(1R)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]N-methylpyrazin-2-amine 106

5-(2,4-dimethoxypyrimidin-5-yl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 107

5-(2,4-dimethoxypyrimidin-5-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 108

N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-6-methyl-3-(methylthio)pyrazin-2-amine 109

6-(2-chloro-4-methoxyphenyl)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine 110

3-(1-ethylbutoxy)-6-(4-methoxy-2-methylphenyl)-N,5-dimethylpyrazin-2-amine 111

5-bromo-6-(2-chloro-4-ethoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine 112

5-bromo-6-(2-chloro-4-ethoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 113

2,5-diethyt-3-(1-ethylbutoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)pyrazine 114

5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 115

5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 116

N-(1-ethylpropyl)-3,6-dimethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 117

methyl 4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzoate 118

4-{5-[(1-ethylpropyl)aminol-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxy-N- methylbenzamide 119

5-bromo-6-(4-isopropoxy-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 120

3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methlpyrazin-2-amine 121

6-ethyl-N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-3-methoxypyrazin-2-amine 122

N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-6-methyl-3-(methylthio)pyrazin-2- amine 123

5-{4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl}-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 124

1-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)-2,2,2- trifluoroethanol 125

5-(2,6-dimethoxypyridin-3-yl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 126

5-(2,6-dimethoxypyridin-3-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 127

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzamide 128

2-{5-[(1-ethylpropyl)aminol-6-methoxy-3-methylpyrazin-2-yl}-5-(trifluoromethoxy)phenol 129

6-(4-isopropoxy-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 130

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxy-N,N- dimethylbenzamide 131

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-N,3,5-trimethoxy-N- methylbenzamide 132

5-bromo-6-(5-bromo-4-isopropoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin- 2-amine 133

2,5-diethyl-3-(1-ethylpropoxy)-6-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]pyrazine 134

N-(1-ethylpropyl)-5-(6-isopropyl-4-methoxypyridin-3-yl)-3-methoxy-6-methylpyrazin-2-amine 135

5-(2-chloro-6-isopropylpyridin-3-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 136

5-bromo-3-(1-ethylbutoxy)-6-(4-isopropyl-2-methoxyphenyl)-N-methylpyrazin-2-amine 137

5-bromo-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-N-methylpyrazin-2-amine 138

5-bromo-6-(4-isopropyl-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine 139

3-ethoxy-6-(4-isopropyl-2-methoxyphenyl)-N,5- dimethylpyrazin-2-amine140

6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine 141

3-(1-ethylbutoxy)-6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethytpyrazin-2-amine 142

N²-(1-ethylpropyt)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazine-2,3-diamine 143

N²-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-6-methylpyrazine-2,3-diamine 144

5-bromo-N³-(1-ethylpropyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N²-methylpyrazine-2,3- diamine 145

5-(4-chloro-2,6-dimethoxyphenyl)-N²-(1-ethylpropyl)-6-methylpyrazine-2,3-diamine 146

N²-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N³,N³,-6-trimethylpyrazine- 2,3-diamine 147

N²-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyrazine-2,3- diamine 148

5-ethyl-N³-(1-ethylpropyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N²-methylpyrazine-2,3- diamine 149

N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-3-methoxy-6-methylpyrazin-2- amine 150

N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyrazin-2- amine 151

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine 152

N-(1-ethylpropyl)-5-[4-(1-fluoro-1-methylethyl)-2,6-dimethoxyphenyl]-3-methoxy-6-methylpyrazin-2- amine 153

N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazin-2-amine d_6_(—) 154

N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxy-6-methylpyrazin-2-amine 155

6-ethyl-N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxypyrazin-2-amine 156

6-ethyl-N-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-3-methoxypyrazin-2-amine 157

N-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-3-methoxy-6-methylpyrazin-2-amine 158

N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-pyrrolidin-1-ylpyridin-3-yl)-6-methylpyrazin-2-amine 159

5-[2,6-dimethoxy-4-(1,2,2,2-tetrafluoroethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 160

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-pyrrolidin-1-ylpyridin-3-yl)pyrazin-2-amine 161

(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)methanol 162

5-[6-(dimethylamino)-2-methylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 163

5-[2,6-dimethoxy-4-(1-methoxyethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 164

5-[4-(1-ethoxyethyl)-2,6-dimethoxyphenyt]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 165

5-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 166

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-methoxyphenyltrifluoromethanesulfonate 167

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-methoxybenzonitrile 168

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzaldehyde O- methyloxime 169

N-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methyl-3- (methylthio)pyrazin-2-amine170

5-(4-chloro-2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine 171

N-(1-ethylpropyl)-5-[2-methoxy-4- (trifluoromethoxy)phenyl]-6-methyl-3-(methylthio)pyrazin-2-amine 172

5-(2,4-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine 173

5-(2,6-dimethoxypyridin-3-yl)-N-(1-ethytpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine 174

N-(1-ethylpropyl)-5-(4-nuoro-2-methoxyphenyl)-6-methyl-3-(methylthio)pyrazin-2-amine 175

5-[2-chloro-4-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine 176

N-(1-ethylpropyl)-5-mesityl-6-methyl-3- (methylthio)pyrazin-2-amine

[0245] TABLE III Compound # Structure IUPAC Name 177

[6-(6-Dimethylamino-4-pyridin-3- yl)-5-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine 178

[6-(6-Dimethylamine-2,4-dimethyl-pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)- pyrazin-2-yl]-methyl-amine179

[5-Ethyl-6-[2(ethyl-methyl-amino)-6- isopropyl-pyridin-3-yl]-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine 180

2-({3-[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl}-6-isopropyl-pyridin-2-yl}-methyl-amino)ethanol 181

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-morpholin-4-yl-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine 182

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-pyrrolidin-1-yl-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine183

{-Ethyl-3-(1-ethyl-propoxy)-6-[6- isopropyl-2-(2-methoxy-ethylamino)-pyridin-3-yl]-pyrazin-2-yl}-methyl-amine 184

[5-Ethyl-6-(5-ethyl-6-(5-ethyl-6-isopropylamino-2-methyl-pyridin-3-yl)-3-1-ethyl-propoxy)- pyrazin-2-yl]-methyl-amine 185

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-methylamino-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine 186

[5-Ethyl-6-(2-ethylamino-6-isopropyl-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin- 2-yl]-methyl-amine 187

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-isopropylamino-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine 188

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6′- isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-pyrazin-2-yl]- methyl-amine 189

3-{3-[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-isopropyl- pyridin-2-ylamion}-propan-1-ol190

[6-(2-Azetidin-1-yl-5-bromo-6-isopropyl-pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)- pyrazin-2-yl]-methyl-amine191

[6-(2-Azetidin-1-yl-5-bromo-6-isopropyl-pyridin-2-yl)-5-ethyl-3-(1-ethyl-propoxy)- pyrazin-2-yl]-methyl-amine192

{5-Ethyl-3-(1-ethyl-propoxy)-6-[6-isopropyl-2-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-pyrazin-2-yl}-methyl-amine 193

(1-Ethyl-propyl)-[3-methoxy-6-methyl-5-(2,3,4-trimethoxy-phenyl)-pyrazin-2-yl]- amine 194

[6-(-Dimethylamino-4-methoxy-pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin- 2-yl]-methyl-amine 195

Trifluoro-methanesulfonic acid 5-[3- ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-methyl- pyridin-2-yl ester 196

[6-(5-Bromo-6-dimethylamino-4- methoxy-pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine 197

[5-Ethyl-6-(5-ethyl-6-isopropyl-2-pyrrolidin-1-yl-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine 198

2-(4-{3-[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-isopropyl-pyridin-2-yl}-piperazin-1-yl)-ethanol 199

N1-{3-[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-isopropyl-pyridin-2-yl}-N1-methyl-ethane-1,2- diamine 200

2-{3-[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-isopropyl- pyridin-2-yloxy}-acetamide 201

2-{3[3-Ethyl-5-(1-ethyl-propoxy)-6-methylamino-pyrazin-2-yl]-6-isopropyl- pyridin-2-yloxy}-ethanol 202

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-piperazin-1-yl-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine 203

[5-Ethyl-3-(1-ethyl-propoxy)-6-(6-isopropyl-2-piperazin-1-yl-pyridin-3-yl)- pyrazin-2-yl]-methyl-amine 204

[5-Ethyl-3-(1-ethyl-propoxy)-6-(2-methyl-6-morpholin-4-yl-pyridin-3-yl)-pyrizin-2- yl]-methyl-amine 205

[6-(6-Dimethylamino-4-methoxy-5-methyl-pyridin-3-yl)-3-(1-ethyl-propoxy)-5-methyl-pyrazin-2-yl]-methyl-amine 206

[6-(6-Dimethylamino-4-methoxy-pyridin-3-yl)-3-(1-ethyl-propoxy)-5-methyl- pyrazin-2-yl]-methyl-amine 207

[5-Ethyl-6-(5-ethyl-2-methyl-6- morpholin-4-yl-pyridin-3-yl)-3-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl-amine 208

[6-(5-Bromo-6-dimethylamino-2-methyl-pyridin-3-yl)-5-ethyl-3-(1-ethyl-propoxy)- pyrazin-2-yl]-methyl-amine209

[6-(6-Dimethylamino-4-methoxy-5-methyl-pyridin-3-yl)-3-(1-ethyl-propoxy)-5-methyl-pyrazin-2-yl]-methyl-amine 210

[3-Bromo-5-(6-dimethylamino-4- methoxy-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1-ethyl-propyl)-amine 211

{5-[3,6-Diethyl-5-(1-ethyl-propoxy)-pyrazin-2-yl]-4-methoxy-pyridin-2-yl}- dimethyl-amine 212

[5-(6-Dimethylamino-4-methoxy-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(ethyl- propyl)-amine 213

[5-(6-Dimethylamino-4-methoxy-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 214

{5-[3,6-Diethyl-5-(1-ethyl-propoxy)-pyrazin-2-yl]-4-isopropoxy-pyridin-2-yl}- dimethyl-amine 215

[5-(6-Dimethylamino-4-isopropoxy-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 216

[5-(6-Dimethylamino-4-isopropoxy-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin- 2-yl]-(1-ethyl-propyl)-amine217

[3-Bromo-5-(6-dimethylamino-4- isopropoxy-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1-ethyl-propyl)-amine 218

[5-(6-Dimethylamino-4-propoxy-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 219

[5-(4-Cyclopentylocy-6-dimethylamino-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 220

[5-(6-Dimethylamino-4-ethoxy-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 221

[5-(6-Dimethylamino-4-trifluoromethyl-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1- ethyl-propyl)amine 222

[5-(6-Dimethylamino-4-ethyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 223

[5-(6- Dimethylamino-4-ethyl-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 224

[5-(6-Dimethylamino-4-trifluoromethyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin- 2-yl]-(1-ethyl-propyl)-amine225

[5-(6-Diethylamino-4-methoxy-pyridin-3-yl)-3,6-diethyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 226

{3,6-Diethyl-5-[6-(ethyl-methyl-amino)-4-methoxy-pyridin-3-pyridin-3-yl]-pyrazin-2-yl}-(1- ethyl-propyl)-amine227

[3,6-diethyl-5-(4-methoxy-6- methylamino-pyridin-3-yl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine 228

[3,6-Diethyl-5-(6-ethylamino-4-methoxy-pyridin-3-yl)-pyrazin-2-yl]-(1-ethyl- propyl)-amine 229

[3,6-Diethyl-5-(6-isopropylamino-4- methoxy-pyridin-3)-pyrazin-2-yl]-(1-ethyl-propyl)-amine 230

[3-Ethyl-5-(4-ethyl-6-ethylamino-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-1-ethyl- propyl)-amine 231

{5-[6-(Ethyl-methyl-amino)-4-methoxy- pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-(1-ethyl-propyl)-amine 232

[5-(6-Dimethylamino-4-isopropoxy- pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 233

[5-(6-Dimethylamino-4-methoxy-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]- (1-ethyl-propyl)-amine 234

{3-Ethyl-5-[4-ethyl-6-(ethyl-methyl-amino)-pyridin-3-yl]-6-methoxy-pyrazin- 2-yl}-(1-ethyl-propyl)-amine 235

[5-(6-Diethylamino-4-ethyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1-ethyl- propyl)-amine 236

[5-(6-Ethylamino-4-methoxy-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 237

[5-(4-Ethyl-6-ethylamino-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 238

[5-(6-Diethylamino-4-ethyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 239

{5-[4-Ethyl-6-(ethyl-methyl-amino)- pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-(1-ethyl-propyl)-amine 240

[5-(4-Ethyl-6-isopropylamino-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 241

[5-(6-Dimethylamino-4-ethyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 242

[3,6-Diethyl-5-(4-ethyl-6-isopropylamino-pyridin-3-yl)-pyrazin-2-yl]-(1-ethyl- propyl)-amine 243

{-[4-Ethyl-6-(ethyl-propyl-amino)- pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-(1-ethyl-propyl)-amine 244

[5-(6-Dimethylamino-4-ethyl-5-methyl- pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 245

6,6′-Diethyl-N5,N5′-bis-(1-ethyl-propyl)-3,3′-dimthoxy-[2,2′]bipyrazinyl-5,5′- diamine 246

{3,6-Diethyl-5-[4-ethyl-6-(ethyl-methyl-amino)-pyridin-3-yl]-pyrazin-2-yl}-(1- ethyl-propyl)-amine 247

[5-(6-tert-Butylamino-4-ethyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 248

[3-Ethyl-5-(4-ethyl-6-isopropylamino-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 249

{5-[4-Ethyl-6-(isopropyl-methyl-amino)-pyridin-3-yl]-3-methyoxy-6-methyl- pyrazin-2-yl}-(1-ethyl-propyl)-amine250

[5-(6-tert-Butylamino-4-ethyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 251

[5-(4-Ethyl-6-isobutylamino-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 252

[3-Ethyl-5-(6-isopropyl-4-methoxy-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 253

{5-[4-Ethyl-6-(1-ethyl-propylamino)- pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-(1-ethyl-propyl)-amine 254

{-[4-Ethyl-6-(isobutyl-methyl-amino)- pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-(1-ethyl-propyl)-amine 255

{6-Ethyl-5-[4-ethyl-6-(isopropyl-methyl-amino)-pyridin-3-yl]-3-methoxy-pyrazin- 2-yl}-(1-ethyl-propyl)-amine 256

[5-(2-Chloro-4-trifluoromethyl-phenyl)-3,6-diethyl-pyrazin-2-yl]-(1-ethyl-propyl)- amine 257

N2-(1-Ethyl-propyl)-5-(6-isopropyl-2-methoxy-pyridin-3-yl)-6-methyl-pyrazine- 2,3-diamine 258

1-{4-[3-Ethyl-5-(1-ethyl-propoxy)-6- methylamino-pyrazin-2-yl]-2,5-dimethoxy-phenyl}-ethanone 259

[3-(2-Chloro-4-methoxy-phenyl)-5-ethyl-6-(1-ethyl-propoxy)-pyrazin-2-yl]-methyl- amine 260

[3-(6-Dimethylamino-4-methoxy-pyridin-3-yl)-5-ethyl-6-(1-ethyl-propoxy)-pyrazin- 2-yl]-methyl-amine 261

[5-(6-Dimethylamino-2-ethyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 262

[3-Bromo-5-(6-dimethylamino-5- methoxymethyl-2-methyl-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1-ethyl-propyl)- amine 263

[5-(6-Dimethylamino-5-methoxymethyl- 2-methyl-pyridin-3-yl)-3-ethyl-6-methoxy-pyrazin-2-yl]-(1-ethyl- propyl)-amine 264

[3,6-Diethyl-5-(6-isopropyl-2-methoxy-pyridin-3-yl)pyrazin-2-yl]-(1-ethyl- propyl)-amine 265

1-{3-[3,6-Diethyl-5-(1-ethyl- propylamino)-pyrazin-2-yl]isopropyl-pyridin-2-ylamino}-propan-2-ol 266

3-{3-[3,6-Diethyl-5-(1-ethyl- propylamino)-pyrazin-2-yl]-6-isopropyl-pyridin-2-ylamino}propan-1-ol 267

2-{3-[3,6-Diethyl-5-(1-ethyl- propylamino)-pyrazin-2-yl]-6-isopropyl-pyridin-2-ylamino}-ethanol 268

[3-Ethyl-5-(6-isopropyl-2-methoxy-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 269

1-{2-Dimethylamino-5-[6-ethyl-5-(1-ethyl-propylamino)-3-methoxy-pyrazin-2-yl]-6-methyl-pyridin-3-yl}-ethanol 270

1-{4-Ethyl-5-[6-ethyl-5-(1-ethyl-propylamino)-3-methoxy-pyrazin-2-yl]-2- methoxy-phenyl}-ethanol 271

[3,6-Diethyl-5-(6-isopropyl-2- methylamino-pyridin-3-yl)- pyrazin-2-yl]-(1-ethyl-propyl)-amine 272

(1-Ethyl-propyl)-[5-(2-methoxy-4- trifluoromethoxy-phenyl)-6-methyl-pyrazin-2-yl]-amine 273

[3-Bromo-5-(2-methoxy-4- trifluoromethoxy-phenyl)-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 274

[6-Chloro-3-ethyl-5-(6-isopropyl-2-methoxy-pyridin-3-yl)-pyrazin-2-yl]-(1- ethyl-propl)-amine 275

[3,6-Diethyl-5-(6-ethyl-2-methoxy- pyridin-3-yl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine 276

[6-Chloro-3-ethyl-5-(6-isopropyl-2-methylamino-pyridin-3-yl)-pyrazin-2-yl]- (1-ethyl-propyl)-amine 277

[3,6-Diethyl-5-(2-ethyl-6-isopropyl-pyridin-3-yl)-pyrazin-2-yl]-(1-ethyl- propyl)-amine 278

[3-Ethyl-5-(6-isopropyl-2-methoxy-pyridin-3-yl)-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 279

[3-Ethyl-5-(2-ethyl-6-isopropyl-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1-ethyl- propyl)-amine 280

[5-(2-Ethyl-6-isopropyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 281

2-{3-[5-(1-Ethyl-propylamino)-6- methoxy-3-methyl-pyrazin-2-yl]-6-isopropyl-pyridin-2-ylamino}-ethanol 282

3-{3-[5-(1-Ethyl-propylamino)-6- methoxy-3-methyl-pyrazin-2-yl]-6-isopropyl-pyridin-2-ylamino}-propan-1- ol 283

(1-Ethyl-propyl)-[5-(6-isopropyl-2-morpholin-4-yl-pyridin-3-yl)-3-methoxy- 6-methyl-pyrazin-2-yl]-amine 284

(1-Ethyl-propyl)-{5-[6-isopropyl-2-(2-methoxy-ethylamino)-pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}-amine 285

(1-Ethyl-propyl)-{5-[6-isopropyl-2-(3-morpholin-4-yl-propylamino)-pyridin-3-yl]-3-methoxy-6-methyl-pyrazin-2-yl}- amine 286

(1-Ethyl-propyl)-[5-(6-isopropyl-2-methylamino-pyridin-3-yl)-3-methoxy-6- methyl-pyrazin-2-yl]-amine 287

[3-Ethoxy-5-(2-methoxy-4- trifluoromethoxy-pheyl)-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 288

[3-Ethyl-5-(2-ethyl-6-isopropyl-pyridin-3-yl)-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 289

[3-Bromo-5-(6-dimethylamino-4-ethyl-pyridin-3-yl)-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 290

{3-Bromo-5-[4-ethyl-6-(ethyl-methyl-amino)-pyridin-3-yl]-6-methyl-pyrazin-2- yl}1-ethyl-propyl)-amine 291

N2-(1-Ethyl-propyl)-5-(2-methyoxy-4-trifluoromethoxy-phenyl)-6,N3-dimethyl- pyrazine-2,3-diamine 292

[3-Ethyl-5-(6-isopropyl-2-methylamino-pyridin-3-yl)-6-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 293

3-{3-[6-Ethyl-5-(1-ethyl-propylamino)-3-methoxy-pyrazin-2-yl]-6-isopropyl- pyridin-2-ylamino}-propan-1-ol 294

Allyl-{3-bromo-5-[4-ethyl-6-(ethyl-methyl-amino)-pyridin-3-yl]-6-methyl-pyrazin-2-yl}(1-ethyl-propyl)-amine 295

6-Ethyl-5-[6-ethyl-5-(1-ethyl- propylamino)-3-methyl-pyrazin-2-yl]-2-isopropyl-2H-pyridin-1-ol 296

N-{3-[5-(1-Ethyl-propylamino)-6- methoxy-3-methyl-pyrazin-2-yl]-6-isopropyl-pyridin-2-yl}-N′,N′-dimethyl- propane-1,3-diamine 297

1-[3-(1-Ethyl-propylamino)-6-(2- methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyrazin-2-yl]-ethanone 298

1-[3-(1-Ethyl-propylamino)-6-(2- methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyrazin-2-yl]-ethanol 299

[5-(6-Dimethylamino-4-trifluoromethyl- pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine 300

[5-(4-Chloro-6-isopropyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 301

[6-Ethyl-5-(2-ethyl-6-isopropyl-pyridin-3-yl)-3-methoxy-pyrazin-2-yl]-(1-ethyl- propyl)-amine 302

[3-Bromo-5-(6-isopropyl-2-methoxy-pyridin-3-yl)-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 303

[6-Ethyl-5-(6-isopropyl-2-methylamino-pyridin-3-yl)-3-methoxy-pyrazin-2-yl]-(1- ethyl-propyl)-amine 304

3-{3-[3-Ethyl-5-(1-ethyl-propylamino)-6-methoxy-pyrazin-2-yl]-6-isopropyl- pyridin-2-ylamino}-propan-1-ol 305

{6-Ethyl-5-[6-isopropyl-2-(3-morpholin-4-yl-propylamino)-pyridin-3-yl]-3-methoxy-pyrazin-2-yl}-(1-ethyl-propyl)-amine 306

[5-(4-Ethyl-6-isopropyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 307

[5-(2-Ethyl-6-isopropoxy-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 308

[6-Ethyl-5-(6-isopropyl-2-methyl-pyridin-3-yl)-3-methoxy-pyrazin-2-yl]-(1-ethyl- propyl)-amine 309

(1-Ethyl-propyl)-[5-(6-isopropyl-2- methyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]amine 310

(1-Ethyl-butyl)-[5-(2-ethyl-6-isopropyl-pyridin-3-yl)-3-methoxy-6-methyl- pyrazin-2-yl]-amine 311

{6-Ethyl-5-[4-ethyl-6-(ethyl-methyl-amino)-pyridin-3-yl]-3-methoxy-pyrazin- 2-yl}(1-ethyl-propyl)-amine 312

(1-Ethyl-butyl)-[5-(6-isopropyl-2-methylamino-pyridin-3-yl)-3-methoxy-6- methyl-pyrazin-2-yl]-amine 313

[5-(2-Ethylamino-6-isopropyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1- ethyl-propyl)-amine 314

[5-(2-Dimethylamino-6-isopropyl-pyridin-3-yl)-3-methoxy-6-pyrazin-2-yl]- (1-ethyl-propyl)-amine 315

(1-Ethyl-butyl)-{5-[6-isopropyl-2-(3-morpholin-4-yl-propylamino)-pyridin-3-yl]methoxy-6-methyl-pyrazin-2-yl}- amine 316

[5-(4-Ethyl-6-isopropoxy-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine 317

[5-(6-Ethoxy-4-ethyl-pyridin-3-yl)-3-methoxy-6-methyl-pyrazin-2-yl]-(1-ethyl- propyl)-amine

Example 30 Assay for CRF Receptor Binding Activity

[0246] As discussed above, the following assay is defined herein as astandard in vitro CRF receptor binding assay. The pharmaceutical utilityof compounds of this invention is indicated by the following assay forCRF1 receptor activity.

[0247] The CRF receptor binding is performed using a modified version ofthe assay described by Grigoriadis and De Souza (Methods inNeurosciences, Vol. 5, 1991). IMR-32 human neuroblastoma cells, a cellline that can be induced to express the CRF1 receptor, are cultured ingrowth medium consisting of EMEM w/Earle's BSS (JRH Biosciences, Cat#51411) supplemented with 10% Fetal Bovine Serum, 25 mM HEPES (pH 7.2), 1mM Sodium Pyruvate, and Non-Essential Amino Acids (JRH Biosciences, Cat#58572). Stock cultures of cells are grown to confluence and subculturedtwice per week at split ratios of 1:2 to 1:4 (cells are dislodged duringsubculturing using No-Zyme, JRH Biosciences, Cat# 59226). To induce CRF1receptor expression, the cells are grown to approximately 80% confluenceand then changed to growth media containing 2.5 μM5-bromo-2′deoxyuridine (BrdU, Sigma, Cat# B9285). Growth mediacontaining BrdU is replaced every 3-4 days and the cells are harvestedvia centrifugation (using No-Zyme) after 10 days of BrdU treatment.Harvested cells are stored frozen at −80° C. until needed for thepreparation of membrane homogenates.

[0248] To prepare receptor-containing membranes cells are homogenized inwash buffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4) andcentrifuged at 48,000×g for 10 minutes at 4° C. The pellet isre-suspended in wash buffer and the homogenization and centrifugationsteps are performed once more.

[0249] Membrane pellets (containing CRF receptors) are resuspended andbrought to a final concentration of 1.0 mg membrane protein/ml inbinding buffer (Tris buffer above with 0.1% BSA and 0.1 mM bacitracin).For the binding assay, 150 microliters of the membrane preparation isadded to 96 well microtube plates containing 50 microliters of ¹²⁵I-CRF(SA 2200 Ci/mmol, final concentration of 100 pM) and 2 microliters oftest compound. Binding is carried out at room temperature for 2 hours.Plates are then harvested using 50 mM Tris buffer pH 7.4, on a BRANDEL96 well cell harvester and filters (soaked in 1% PEI for 1.5 hours) arecounted for gamma emissions on a Wallac 1205 BETAPLATE liquidscintillation counter. Non-specific binding is defined by 2 micromolarcold CRF. K_(i) values are calculated with the non-linear curve fittingprogram RS/1 (BBN Software Products Corp., Cambridge, Mass.).

[0250] The binding affinity for the compounds of Formula I expressed asa K_(i) value, generally ranges from about 0.5 nanomolar to about 10micromolar. Preferred compounds of Formula I exhibit K_(i) values ofless than or equal to 1.5 micromolar, more preferred compounds ofFormula I exhibit K_(i) values of less than 500 nanomolar, still morepreferred compounds of Formula I exhibit K_(i) values of less than 100nanomolar, and most preferred compound of Formula I exhibit K_(i) valuesof less than 10 nanomolar.

[0251] Compounds in Table I which have an asterisk in the column labeled“K_(i)<1 μM” have been tested in this assay and found to exhibit a K_(i)value of less than 1 micromolar. All compounds shown in Table II havealso been tested in this assay and found to exhibit a K_(i)value of lessthan 1 micromolar.

Example 31 Preparation of Radiolabeled Probe Compounds of Formula I

[0252] The compounds of Formula I are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SR₁International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

[0253] Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound ofFormula I as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 32 Receptor Autoradiography

[0254] Receptor autoradiography (receptor mapping) is carried out invitro as described by Kuhar in sections 8.1.1 to 8.1.9 of CurrentProtocols in Pharmacology (1998) John Wiley & Sons, New York, usingradiolabeled compounds of Formula I prepared as described in thepreceding Examples.

Example 33 Additional Aspects of Preferred Compounds of Formula I

[0255] The most preferred compounds of Formula I are suitable forpharmaceutical use in treating human patients. Accordingly, suchpreferred compounds are non-toxic. They do not exhibit single ormultiple dose acute or long-term toxicity, mutagenicity (e.g., asdetermined in a bacterial reverse mutation assay such as an Ames test),teratogenicity, tumorogenicity, or the like, and rarely trigger adverseeffects (side effects) when administered at therapeutically effectivedosages.

[0256] Preferably, administration of such preferred compounds of FormulaI at certain doses (e.g., doses yielding therapeutically effective invivo concentrations or preferably doses of 10, 50, 100, 150, or 200mg/kg—preferably 150 mg/kg—administered parenterally or preferablyorally) does not result in prolongation of heart QT intervals (i.e., asdetermined by electrocardiography, e.g., in guinea pigs, minipigs ordogs). When administered daily for 5 or preferably ten days, such dosesof such preferred compounds also do not cause liver enlargementresulting in an increase of liver to body weight ratio of more than100%, preferably not more than 75% and more preferably not more than 50%over matched controls in laboratory rodents (e.g., mice or rats). Inanother aspect such doses of such preferred compounds also preferably donot cause liver enlargement resulting in an increase of liver to bodyweight ratio of more than 50%, preferably not more than 25%, and morepreferably not more than 10% over matched untreated controls in dogs orother non-rodent animals.

[0257] In yet another aspect such doses of such preferred compounds alsopreferably do not promote the release of liver enzymes (e.g., ALT, LDH,or AST) from hepatocytes in vivo. Preferably such doses do not elevatesuch enzymes by more than 100%, preferably not by more than 75% and morepreferably not by more than 50% over matched untreated controls inlaboratory rodents. Similarly, concentrations (in culture media or othersuch solutions that are contacted and incubated with cells in vitro)equivalent to two, fold, preferably five-fold, and most preferablyten-fold the minimum in vivo therapeutic concentration do not causerelease of any of such liver enzymes from hepatocytes in vitro.

[0258] Because side effects are often due to undesirable receptoractivation or antagonism, preferred compounds of Formula I exert theirreceptor-modulatory effects and bind to the CRF1 receptor with highselectivity. This means that they do not bind to certain other receptors(i.e., other than CRF receptors) with high affinity, but rather onlybind to, activate, or inhibit the activity of such other receptors withaffinity constants of greater than 100 nanomolar, preferably greaterthan 1 micromolar, more preferably greater than 10 micromolar and mostpreferably greater than 100 micromolar. Such receptors preferably areselected from the group including ion channel receptors, includingsodium ion channel receptors, neurotransmitter receptors such as alpha-and beta-adrenergic receptors, muscarinic receptors (particularly m1,m2, and m3 receptors), dopamine receptors, and metabotropic glutamatereceptors; and also include histamine receptors and cytokine receptors,e.g., interleukin receptors, particularly IL-8 receptors. The group ofother receptors to which preferred compounds do not bind with highaffinity also includes GABAA receptors, bioactive peptide receptors(including NPY and VIP receptors), neurokinin receptors, bradykininreceptors (e.g., BK1 receptors and BK2 receptors), and hormone receptors(including thyrotropin releasing hormone receptors andmelanocyte-concentrating hormone receptors).

Example 34 Absence of Sodium Ion Channel Activity

[0259] Preferred compounds of Formula I do not exhibit activity assodium ion channel blockers. Sodium channel activity may be measured astandard in vitro sodium channel binding assays such as the assay givenby Brown et al. (J. Neurosci. (1986) 265: 17995-18004). Preferredcompounds of Formula I exhibit less than 15 percent inhibition, and morepreferably less than 10 percent inhibition, of sodium channel specificligand binding when present at a concentration of 4 μM. The sodium ionchannel specific ligand used may be labeled batrachotoxinin,tetrodotoxin, or saxitoxin. Such assays, including the assay of Brownreferred to above, are performed as a commercial service by CEREP, INC.,Redmond, Wash.

[0260] Alternatively, sodium ion channel activity may be measured invivo in an assay of anti-epileptic activity. Anti-epileptic activity ofcompounds may be measured by the ability of the compounds to inhibithind limb extension in the supramaximal electroshock model. Male HanWistar rats (150-200 mg) are dosed i.p. with a suspension of 1 to 20 mgof test compound in 0.25% methylcellulose 2 hr. prior to test. A visualobservation is carried out just prior to testing for the presence ofataxia. Using auricular electrodes a current of 200 mA, duration 200milliseconds, is applied and the presence or absence of hind limbextension is noted. Preferred compounds of Formula I do not exhibitsignificant anti-epileptic activity at the p<0.1 level of significanceor more preferably at the p<0.05 level of significance as measured usinga standard parametric assay of statistical significance such as astudent's T test.

Example 35 Optimal In Vitro Half-Life

[0261] Compound half-life values (t_(1/2) values) may be determined viathe following standard liver microsomal half-life assay. Livermicrosomes are obtained from pooled liver samples and prepared so thatthe P-450 enzyme content is approximately 0.5 mmol/mg protein. Reactionsare preformed in a 5 ml well deep-well plate as follows:

[0262] Phosphate buffer: 19 mL 0.1 M NaH₂PO₄, 81 mL 0.1 Na₂HPO₄, pH 7.4with H₃PO₄.

[0263] CoFactor Mixture: 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4mL 100 mM MgCl₂.

[0264] Glucose-6-phosphate dehydrogenase: 214.3 microlitersglucose-6-phosphate dehydrogenase, 1285.7 microliters distilled water

[0265] Starting Reaction Mixture: 3 mL CoFactor Mixture, 1.2 mLGlucose-6-phosphate dehydrogenase

[0266] 6 identical sample wells each containing 25 microlitersmicrosomes, 5 microliters test compound (from a 100 uM stock), and 399microliters 0.1 M phosphate buffer, pH 7.4, are prepared. A seventh wellcontaining 25 microliters microsomes, 399 microliters 0.1 M phosphatebuffer, pH 7.4, and 5 microliters (from a 100 uM stock) of a compound,e.g. diazapam, clozapine, with known metabolic properties is used as apositive control. Reactions are preincubated at 39° C. for 10 minutes.71 microliters Starting Reaction Mixture is added to 5 of the 6 reactionwells and to the positive control well, 71 microliters 100 mM MgCl₂ isadded to the sixth reaction well, which is used as a negative control.At each time point (0, 1, 3, 5, and 10 minutes) 75 microliters reactionis pipetted into a 96-well deep-well plate reaction well containing 75microliters ice-cold acetonitrile. Samples are vortexed and centrifuged10 minutes at 6000 rpm (Sorval T 6000D rotor). Supernatant, 75microliters from each reaction well, is transferred to a 96-well platecontaining 150 microliters internal standard per well. The remainingtest compound is quantitated via LCMS. Compound concentration vs time isplotted and commercially available statistical software is used toextrapolate to the t_(1/2) value of the test compound.

[0267] Preferred compounds of Formula I exhibit in vitro t_(1/2) valuesof greater than 10 minutes and less than 4 hours. Most preferredcompounds of Formula I exhibit in vitro t_(1/2) values of between 30minutes and 1 hour in human liver microsomes.

Example 36 MDCK Toxicity

[0268] Compounds causing acute cytotoxicity will decrease ATP productionby Madin Darby canine kidney (MDCK) cells in the following assay.

[0269] MDCK cells, ATCC no. CCL-34 (American Type Culture Collection,Manassas, Va.) are maintained in sterile conditions following theinstructions in the ATCC production information sheet. The PACKARD,(Meriden, Conn.) ATP-LITE-M Luminescent ATP detection kit, product no.6016941, allows measurement ATP production in MDCK cells.

[0270] Prior to assay 1 microliter of test compound or control sample ispipetted into PACKARD (Meriden, Conn.) clear bottom 96-well plates. Testcompounds and control samples are diluted in DMSO to give finalconcentration in the assay of 10 micromolar, 100 micromolar, or 200micromolar. Control samples are drug or other compounds having knowntoxicity properties.

[0271] Confluent MDCK cells are trypsinized, harvested, and diluted to aconcentration of 0.1×10⁶ cells/ml with warm (37° C.) VITACELL MinimumEssential Medium Eagle (ATCC catalog # 30-2003). 100 microliters ofcells in medium is pipetted into each of all but five wells of each96-well plate. Warm medium without cells (100 ul) is pipetted in theremaining five wells of each plate. These wells, to which no cells areadded, are used to determine the standard curve. The plates are thenincubated at 37° C. under 95% 02, 5% CO₂ for 2 hours with constantshaking. After incubation, 50 microliters of mammalian cell lysissolution is added per well, the wells are covered with PACKARD TOPSEALstickers, and plates are shaken at approximately 700 rpm on a suitableshaker for 2 minutes.

[0272] During the incubation, PACKARD ATP LITE-M reagents are allowed toequilibrate to room temperature. Once equilibrated the lyophilizedsubstrate solution is reconstituted in 5.5 ml of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. For the five control wells, 10microliters of serially diluted PACKARD standard is added to each of thefive standard curve control wells to yield a final concentration in eachsubsequent well of 200 nM, 100 nM, 50 nM, 25 nM, and 12.5 nM.

[0273] PACKARD substrate solution (50 ul) is added to all wells. Wellsare covered with PACKARD TOPSEAL stickers, and plates are shaken atapproximately 700 rpm on a suitable shaker for 2 minutes. A whitePACKARD sticker is attached to the bottom of each plate and samples aredark adapted by wrapping plates in foil and placing in the dark for 10minutes. Luminescence is then measured at 22° C. using a luminescencecounter, e.g. PACKARD TOPCOUNT Microplate Scintillation and LuminescenseCounter or TECAN SPECTRAFLUOR PLUS.

[0274] Luminescence values at each drug concentration are compared tothe values computed from the standard curve for that concentration.Preferred test compounds exhibit luminescence values 80% or more of thestandard, or preferably 90% or more of the standard, when a 10micromolar (uM) concentration of the test compound is used. When a 100micromolar concentration of the test compound is used, preferred testcompounds exhibit luminescence values 50% or more of the standard, ormore preferably 80% or more of the standard.

What is claimed is:
 1. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein: G is oxygen orNH; R_(X) is straight or branched chain C₁₋₈alkyl; R₁ and R₃ areindependently selected from hydrogen, C₁₋₄ alkyl, halogen, C₁₋₂haloalkyl, C₁₋₂haloalkoxy, mono- and di-C₁₋₄alkylamino, C₁₋₄alkoxy, andC₁₋₄ alkylthio; R₅ is halogen, C₁₋₄alkyl, or C₁₋₄alkoxy; R₆ is hydrogen,halogen, C₁₋₂alkyl, or C₁₋₂alkoxy; R₇ is halogen, halogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₂ haloalkyl, C₁₋₂haloalkoxy, mono- anddi-C₁₋₄alkylamino, mono- and di-(C₁₋₂alkyl)aminoC₁₋₄alkyl,C₁₋₂alkoxyC₁₋₄alkyl, C₁₋₂alkoxycarbonyl, C₁₋₂alkylcarboxaminde,—C(═O)NH₂, hydroxyC₁₋₂alkyl, trifluoromethylsulfonyl,2,2,2-trifluoroethanol, or a 4-7 membered heterocycloalkyl groupcontaining 1 or 2 atoms independently chosen from N, O, and S; R₈ ishydrogen, halogen, C₁₋₂alkyl, or C₁₋₂alkoxy; and J is N or CR₉ where R₉is hydrogen, halogen or C₁₋₂alkyl.
 2. A compound or salt according toclaim 1 wherein R₁ and R₃ are not hydrogen.
 3. A compound or saltaccording to claim 1 wherein J is nitrogen and R₆ is hydrogen.
 4. Acompound or salt according to claim 1 wherein J is CH and R₆ ishydrogen.
 5. A compound or salt according to claim 1 wherein G is NH andRx is 1-ethyl propyl.
 6. A compound or salt according to claim 5 whereinR₁ is cyano, methoxy, or methylthio and R₃ is methyl or ethyl.
 7. Acompound or salt according to claim 1 wherein G is oxygen and R_(X) is1-ethylpropyl, 1-isopropyl-2-methypropyl, 1-propylbutyl, or1-ethylbutyl.
 8. A compound or salt according to claim 7 wherein R₃ ishalogen, C₁₋₂alkyl, or methylamino.
 9. A compound or salt according toclaim 7 wherein R₁ is halogen, methyl, methoxy, ethyl, ethoxy, orC₁₋₂alkylamino.
 10. A compound or salt according to claim 7 wherein R₁is methylamino.
 11. A compound according to claim 1 which is selectedfrom5-ethyl-6-(1-ethylpropoxy)-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2amine;5-bromo-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2amine;3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2amine;2-(4-tert-butyl-2-methoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine;2-(4-tert-butyl-2-methoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine;2,5-diethyl-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)pyrazine;2,5-diethyl-3-(4-isopropyl-2-methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine;2-(2,6-dimethoxypyridin-3-yl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine;2-(2,6-dimethoxypyridin-3-yl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine;2,5-diethyl-3-(4-ethyl-2-methoxyphenyl)-6-(1-ethylpropoxy)pyrazine;2-[2-chloro-4-(difluoromethoxy)phenyl]-3,6-diethyl-5-(1-propylbutoxy)pyrazine;2,5-diethyl-3-(1-ethylbutoxy)-6-(4-isopropyl-2-methoxyphenyl)pyrazine;2,5-diethyl-3-(1-ethylpropoxy)-6-(2-fluoro-4,6-dimethoxyphenyl)pyrazine;and2,5-diethyl-3-(2-fluoro-4,6-dimethoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine;2,5-diethyl-3-(4-isopropyl-2-methoxyphenyl)-6-(1-propylbutoxy)pyrazine;5-(1-ethylpropoxy)-2-[2-methoxy-4-(trifluoromethoxy)phenyl]-3-methylpyrazine;2-chloro-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methylpyrazine;2-(1-ethylpropoxy)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazine;6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2amine;5-[3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazin-2-yl]-6-methoxy-N,N-dimethylpyridin-2-amine;5-bromo-6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylpropoxy)-N-methylpyrazin-2amine;2-chloro-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-5-methylpyrazine;3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine;5-(1-ethylpropoxy)-2-[2-methoxy-4-(trifluoromethyl)phenyl]-3-methylpyrazine;5-bromo-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2amine;2-chloro-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methylpyrazine;3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2-amine;3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethylpyrazin-2-amine;and5-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methyl-3-(1-propylbutoxy)pyrazin-2amine;6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2amine;5-bromo-6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylbutoxy)-N-methylpyrazin-2amine;6-[4-(difluoromethoxy)-2-methoxyphenyl]-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine;5-bromo-6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2amine;6-(4-ethoxy-2-methoxy-5-methylphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine;5-bromo-6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine;5-bromo-6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;5-bromo-3-ethoxy-6-(4-ethoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine;6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine;6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine;6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine;5-bromo-6-(4-ethoxy-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine;6-(4-ethoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;5-bromo-3-(1-ethylbutoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine;6-(4-ethoxy-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine;5-bromo-6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-25amine;6-(5-bromo-4-ethoxy-2-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine;6-(4-ethoxy-2-methoxy-5-methylphenyl)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine;5-bromo-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methylpyrazin-2amine;5-bromo-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methyl-3-(1-propylbutoxy)pyrazin-2amine;3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethylpyrazin-2-amine;6-[2-methoxy-4-(trifluoromethyl)phenyl]-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine;5-bromo-3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine;3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N,1-dimethylpyrazin-2-amine;3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N,5-dimethylpyrazin-2-amine;-ethyl-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N-methylpyrazin-2amine;3-(1-ethylbutoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine;6-(2-ethyl-4-methoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile;6-(2,4-dimethoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile;5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2amine;6-[2-chloro-4-(trifluoromethyl)phenyl]-3-[(1-ethylpropyl)amino]-5-methylpyrazine-225carbonitrile;6-(2,6-dimethoxypyridin-3-yl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2-carbonitrile;3-[(1-ethylpropyl)amino]-6-mesityl-5-methylpyrazine-2-carbonitrile;6-(4-chloro-2,6-dimethoxyphenyl)-3-[(1-ethylpropyl)amino]-5-methylpyrazine-2carbonitrile;3-[(1-ethylpropyl)amino]-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-methylpyrazine-2carbonitrile;5-[2-chloro-4-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2amine;5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2amine;5-[6-(dimethylamino)-2-ethylpyridin-3-yl]-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine;5-bromo-6-(2-chloro-4-isopropoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;5-bromo-6-(2-chloro-4-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;6-(2-chloro-4-methoxyphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine;6-(2-chloro-4-isopropoxyphenyl)-3-(1-ethylpropoxy)-N,5-dimethylpyrazin-2-amine;N-(1-ethylpropyl)-5-mesityl-3-methoxy-6-methylpyrazin-2-amine;5-[6-(dimethylamino)-2,4-dimethylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methylphenyl)-N,5-dimethylpyrazin-2-amine;5-bromo-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]-N-methylpyrazin-2amine;N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxypyrazin-2-amine;5-bromo-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)-N-methylpyrazin-2amine;5-bromo-6-(2-chloro-4-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine;6-(2-chloro-4-methoxyphenyl)-5-ethyl-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;5-bromo-6-(2-chloro-4-methoxyphenyl)-3-(1-ethylbutoxy)-N-methylpyrazin-2-amine;6-(2-chloro-4-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine;2,5-diethyl-3-(1-ethylpropoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)pyrazine;3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2-amine;3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2amine;5-bromo-3-{[(1S)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine;3-{[(1R)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N,5-dimethylpyrazin-2-amine;3-{[(1R)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2amine;5-bromo-3-{[(1R)-1-ethylbutyl]oxy}-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-methylpyrazin-2-amine;5-(2,4-dimethoxypyrimidin-5-yl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-(2,4-dimethoxypyrimidin-5-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine;N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-6-methyl-3-(methylthio)pyrazin-2amine;6-(2-chloro-4-methoxyphenyl)-3-(1-ethylbutoxy)-N,5-dimethylpyrazin-2-amine;3-(1-ethylbutoxy)-6-(4-methoxy-2-methylphenyl)-N,5-dimethylpyrazin-2-amine;5-bromo-6-(2-chloro-4-ethoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;5-bromo-6-(2-chloro-4-ethoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine;2,5-diethyl-3-(1-ethylbutoxy)-6-(6-isopropyl-2-methoxypyridin-3-yl)pyrazine;5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-61methylpyrazin-2-amine;N-(1-ethylpropyl)-3,6-dimethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2amine;methyl4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzoate;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxy-N-methylbenzamide;5-bromo-6-(4-isopropoxy-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine;3-(1-ethylpropoxy)-6-(4-isopropoxy-2-methoxyphenyl)-N-methylpyrazin-2-amine;6-ethyl-N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-3-methoxypyrazin-2-amine;N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-6-methyl-3-(methylthio)pyrazin-2amine;5-{4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl}-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;1-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)-2,2,2-trifluoroethanol;5-(2,6-dimethoxypyridin-3-yl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-(2,6-dimethoxypyridin-3-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzamide;2-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-5-(trifluoromethoxy)phenol;6-(4-isopropoxy-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxy-N,N-dimethylbenzamide;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-N,3,5-trimethoxy-N-methylbenzamide;5-bromo-6-(5-bromo-4-isopropoxy-2-methoxyphenyl)-3-(1-ethylpropoxy)-N-methylpyrazin-2-amine;2,5-diethyl-3-(1-ethylpropoxy)-6-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]pyrazine;N²-(1-ethylpropyl)-5-(6-isopropyl-4-methoxypyridin-3-yl)-3-methoxy-6-methylpyrazin-2amine;N²-(2-chloro-6-isopropylpyridin-3-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine;5-bromo-3-(1-ethylbutoxy)-6-(4-isopropyl-2-methoxyphenyl)-N-methylpyrazin-2-3-diamine;5-bromo-3-(1-ethylpropoxy)-6-(4-isopropyl-2-methoxyphenyl)-N-methylpyrazin-2-amine;5-bromo-6-(4-isopropyl-2-methoxyphenyl)-N-methyl-3-(1-propylbutoxy)pyrazin-2-amine;3-ethoxy-6-(4-isopropyl-2-methoxyphenyl)-N, 5-dimethylpyrazin-2-amine;6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethyl-3-(1-propylbutoxy)pyrazin-2-amine;3-(1-ethylbutoxy)-6-(4-isopropyl-2-methoxyphenyl)-N,5-dimethylpyrazin-2-amine;N²-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazine-2,3-diamine;N²-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-6-methylpyrazine-2,3-diamine;5-bromo-N³-(1-ethylpropyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N2-methylpyrazine-2,3-diaamine; 5-(4-chloro-2,6-dimethoxyphenyl)-N2-(1-ethylpropyl)-6-methylpyrazine-2,3-diamine;N²-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N³N³-6-trimethylpyrazine-2,3-diamine;N²-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyrazine-2,3diamine;5-ethyl-N³-(1-ethylpropyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-N²-methylpyrazine-2,3-diamine;N-(1-ethylpropyl)-5-(4-isopropyl-2,6-dimethoxyphenyl)-3-methoxy-6-methylpyrazin-2amine;N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methylpyrazin-2-amine;6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine;N-(1-ethylpropyl)-5-[4-(1-fluoro-1-methylethyl)-2,6-dimethoxyphenyl]-3-methoxy-6-methylpyrazin-2-amine;D6-N-(1-ethylpropyl)-3-methoxy-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazin-2-amine;N-(1-ethylpropyl)-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxy-6-methylpyrazin-2amine;6-ethyl-N-(1-ethylpropyl)-1-(6-isopropyl-2-methoxypyridin-3-yl)-3-methoxypyrazin-2amine;6-ethyl-N-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-3-methoxypyrazin-2-amine;N-(1-ethylpropyl)-5-(4-isopropyl-2-methoxyphenyl)-3-methoxy-6-methylpyrazin-2-amine;N-(1-ethylpropyl)-3-methoxy-1-(2-methoxy-6-pyrrolidin-1-ylpyridin-3-yl)-6-methylpyrazin-2-amine;5-[2,6-dimethoxy-4-(1,2,2,2-tetrafluoroethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-pyrrolidin-1-ylpyridin-3-yl)pyrazin-2amine;(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)methanol;5-[6-(dimethylamino)-2-methylpyridin-3-yl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-[2,6-dimethoxy-4-(1−methoxyethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-[4-(1-ethoxyethyl)-2,6-dimethoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;5-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-methoxyphenyltrifluoromethanesulfonate;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-methoxybenzonitrile;4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxybenzaldehydeO-methyloxime;N-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-6-methyl-3-(methylthio)pyrazin-2-amine;5-(4-chloro-2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2amine;N-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methyl-3-(methylthio)pyrazin-2-amine;5-(2,4-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine;5-(2,6-dimethoxypyridin-3-yl)-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2-amine;N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-6-methyl-3-(methylthio)pyrazin-2-amine;5-[2-chloro-4-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-6-methyl-3-(methylthio)pyrazin-2amine;and N-(1-ethylpropyl)-5-mesityl-6-methyl-3-(methylthio)pyrazin-2-amine,or a pharmaceutically acceptable salt thereof.
 12. A compound or saltaccording to claim 1 wherein, in a standard in vitro CRF receptorbinding assay the compound exhibits a K_(i) value for CRF receptors ofless than or equal to 1 micromolar.
 13. A compound or salt according toclaim 1 wherein, in a standard in vitro CRF receptor binding assay thecompound exhibits a K_(i) value for CRF receptors of less than or equalto 100 nanomolar.
 14. A compound or salt according to claims 1 wherein,in a standard in vitro CRF receptor binding assay, the compound exhibitsa K_(i) value for CRF receptors of less than or equal to 10 nanomolar.15. A method for treating anxiety, depression, or stress comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound or salt according to claim
 1. 16. Amethod for treating irritable bowel syndrome or Crohn's disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or salt according toclaim
 1. 17. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound or salt of claim
 1. 18. Apharmaceutical composition according to claim 17, wherein thecomposition is formulated as an injectable fluid, an aerosol, a cream, agel, a tablet, a pill, a capsule, a syrup or a transdermal patch.
 19. Apackage comprising a pharmaceutical composition of claim 17 in acontainer and further comprising indicia comprising at least one of:instructions for using the composition to treat a patient suffering fromanxiety, or instructions for using the composition to treat a patientsuffering from stress, or instructions for using the composition totreat a patient suffering from depression.
 20. A package comprising apharmaceutical composition of claim 17 in a container and furthercomprising at least one of: instructions for using the composition totreat a patient suffering from irritable bowel syndrome or instructionsfor using the composition to treat a patient suffering from Crohn'sdisease.
 21. A method for demonstrating the presence or absence of CRF1receptors in a biological sample, said method comprising: a) contactingthe biological sample with a labeled compound according to claim 1 underconditions that permit binding of the labeled compound to a CRF1receptor; b) separating unbound labeled compound from bound labeledcompound; and c) detecting the bound labeled compound in the biologicalsample, and therefrom determining the presence or absence of CRF1receptors in the sample.
 22. The method of claim 21 wherein the labeledcompound is detected using autoradiography.
 23. A method of inhibitingthe binding of CRF to a CRF1 Receptor, which method comprises:contacting a solution comprising CRF and a compound or salt of claim 1with a cell expressing the CRF receptor, wherein the compound or salt ispresent in the solution at a concentration sufficient to inhibit invitro CRF binding to EMR32 cells.
 24. The method of claim 23 wherein thecell expressing the CRF receptor is a neuronal cell that is contacted invivo in an animal, and wherein the solution is a body fluid of saidanimal.
 25. The method of claim 23 wherein the animal is a humanpatient.